Spatial analysis of tumor immune microenvironment (TIME) in patients treated with Bintrafusp alfa.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3070-3070
Author(s):  
Houssein Abdul Sater ◽  
Jeffrey Robinson ◽  
Julius Strauss ◽  
Margaret Elena Gatti-Mays ◽  
Jason Redman ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Tumor Control ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Linear Discriminant ◽  
Number Of Patients

3070 Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII receptor (TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In preclinical models, bintrafusp alfa treatment promoted CD8+ T cell and NK cell activation, and both immune cell (IC) populations were required for optimal bintrafusp alfa mediated tumor control. However, the effect of bintrafusp alfa on TIME in humans has not been reported. Methods: In this unplanned interim analysis of a biomarker expansion cohort (NCT 02517398), patients (pts) with advanced non-small cell lung cancer (NSCLC) underwent paired biopsies (bx) before and on treatment with bintrafusp alfa (~ 50 days apart). The objective was to evaluate frequency and localization of tumor infiltrated ICs by IHC. Out of 12 pts, 7 had matched (Pre vs Post) tumor-containing specimens sufficient for multiplex immunofluorescence (MxIF) analysis of TIME. Four pts were excluded as Post bx histology for 3/12 [2 PR (partial response), 1 SD (stable disease)] was negative for tumor (necrosis or fibrosis) and 1/12 did not have a Post bx performed. Results: TIME study shows CD8 T cell infiltrates were increased in Post compared to Pre bx (median 161 vs 62/mm²; interquartile range [IQR] 65–396/mm² vs 31–135/mm²; p = 0·04). While M2 macrophages were also increased (median 800 vs 367/mm²; IQR 776–1131/mm² vs 171–831/mm²; p = 0·04), the ratio of M1/M2 was reversed in pts with SD (↑) compared to pts with PD (↓). Other ICs such as CD4, T-regs, NK cells and M1 macrophages were not changed. On average compared to baseline, M2 macrophages were > 2 fold closer to every other IC in pts with PD, but > 2 fold further from any IC in pts with SD. Tregs were relatively closer to other IC in PD pts. Linear Discriminant Analysis was also performed and results indicate that differential IC densities (mainly M1 macrophages and CD4 T cells) do perform as classifiers between long ( > 5 months) and short ( < 5 months) term responses. Conclusions: This study suggests that bintrafusp alfa not only can enhance intratumoral effector IC infiltrates (CD8) but also has a modulating effect on the spatial distribution of both M1/M2 macrophages within the NSCLC TIME. The differential proximity of M2 macrophages to other IC infiltrates and changes in M1/M2 ratios in association with response suggests that an M1/M2 macrophage balance is directly involved in response and/or resistance to bintrafusp alfa. Given the limited number of patients in this cohort, we intend to study effects of bintrafusp alfa in a larger cohort of patients. Clinical trial information: 02517398 .

M2 Macrophage Infiltration Is Closely Associated with Poor Prognosis for Adult T-Cell Leukemia/Lymphoma (ATLL),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3672-3672 ◽  
Author(s):  
Daisuke Niino ◽  
Yoshihiro Komohara ◽  
Yoshizo Kimura ◽  
Masanori Takeuchi ◽  
Hiroaki Miyoshi ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Poor Prognosis ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
Adult T Cell Leukemia ◽  
Cd163 Expression ◽  
Tumor Area

Abstract Abstract 3672 Background: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by a retrovirus, human T-cell lymphotropic virus type I, and characterized by an aggressive clinical course and poor prognosis. Although several factors associated with this poor prognosis have been identified, including high-level Ki67 antigen expression and high serum levels of calcium, parathyroid hormone-related protein, soluble interleukin-2 receptor, β2-microglobulin, and neuron-specific enolase, the accuracy of current prognostic models for prediction of the outcome of treatment is inadequate, and clinically relevant biomarkers have not been established. Tumor-associated macrophages, which are known to possess the immunosuppressive M2 macrophage phenotype, contribute to tumor growth, invasion, and metastasis by producing various mediators. Macrophage polarization is divided into types M1 and M2 based on the expression of membrane receptors, cytokines, and chemokines. M1 expresses CD80, interleukin (IL)-6, IL-12, and chemokine receptor 7, while M2 expresses CD163, IL10, and chemokine ligand 22. The classically activated M1 macrophages exhibit antitumor functions and the alternatively activated M2 macrophages protumor functions, which contribute to the development and progression of tumors. CD163 is a monocyte/macrophage-restricted membrane protein belonging to the scavenger receptor cysteine-rich domain family and it functions as an endocytic receptor for a hemoglobin-haptoglobin complex. CD163 expression has been associated with an anti-inflammatory M2 macrophage phenotype and is believed to be useful for distinguishing M2 macrophages from pro-inflammatory M1 macrophages. Macrophages, especially M2 polarized macrophages, preferentially express CD163, but no studies have investigated macrophage phenotypes in ATLL. The aim of our study was therefore to investigate CD163 expression, which has been used as a marker for M2 macrophages, and the relationship between macrophage activation and prognosis for ATLL in order to gain new information about the therapeutic implications of this relationship for ATLL. Methods: Between 1985 and 2003, 75 cases of ATLL were examined. The male-to-female ratio was 1.34:1 and the median age 63 years (range: 35–87 years). Advanced clinical stages were identified in 75% of the patients, and lactic dehydrogenase was elevated in 25%. Most patients were treated with combination chemotherapy and the median survival period was 271 days (range: 4–3, 807 days). We performed a retrospective study on the immunohistochemical expression of macrophage markers (CD68, CD163) and their correlation with overall survival for the 75 ATLL patients. Paraffin sections were examined immunohistochemically by using anti-CD68 (PGM1) and anti-CD163 antibodies, and the absolute number of intratumoral macrophages in the ATLL specimens was determined. Kaplan-Meier survival estimates were subjected to comparative univariate analyses using the log-rank test. Cox proportional-hazard regression test was used for the multivariate analysis. P-values of less than 0.05 were considered significant. Results: The number of CD68-positive macrophages in ATLL tissues did not correlate with overall survival (P =0.25), whereas patients with a large number of CD163-positive macrophages (>250 cells/mm2 tumor area; n=37) had worse outcomes than those with a small number (<250 cells/mm2 tumor area; n=36) (P =0.05). Meanwhile, a higher ratio of CD163-positive to CD68-positive macrophages in ATLL significantly correlated with worse overall survival (P =0.039). Multivariate analysis confirmed that high CD163/CD68 ratio was an independent prognostic factor. Conclusions: Considering that high CD163/CD68 ratio reflects the proportion of macrophages polarized to the M2 phenotype, our findings further indicate that activation of macrophages towards the M2 phenotype correlates with worse prognosis. They also suggest that immunohistochemical analysis of M2 macrophages at the time of diagnosis can provide additional relevant prognostic information. However, these findings need to be further explored in future studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IMMU-19. QUINOLINATE-INDUCED IMMUNE SUPPRESSION IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi123-vi123
Author(s):  
Pravin Kesarwani ◽  
Shiva Kant ◽  
Antony Prabhu ◽  
Prakash Chinnaiyan
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Tumor Cells ◽  
Cd8 T Cell ◽  
Tryptophan Metabolism ◽  
T Cell Proliferation ◽  
M2 Macrophage ◽  
Low Grade ◽  
M2 Macrophages ◽  
Metabolic Remodeling

Abstract Glioblastoma continues to be an invariably fatal malignancy with limited treatment options. We performed integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived tumors to provide insight into metabolic programs that may be driving the aggressive phenotype of this malignancy. A persistent theme that emerged was the interplay between metabolic remodeling and immune response. Most notable was a 64-fold accumulation of quinolinate, which represents a downstream intermediary of tryptophan metabolism, in glioblastoma, when compared to low-grade astrocytoma. We discovered a dynamic interaction between cells within the tumor microenvironment that contributes to the generation of quinolinate. Specifically, neither tumor cells nor immune cells demonstrated the capacity to completely metabolize tryptophan. Tumor cells were required to metabolize tryptophan to kynurenine, while only cells of monocyte lineage, including M1/M2 macrophages and microglial cells, demonstrated the capacity to generate quinolinate from tumor-generated kynurenine. We next sought to determine if the observed accumulation of quinolinate in glioblastoma had immune consequences. We discovered a novel role quinolinate plays in increasing (~50%) immunosuppressive M2 macrophage (CD45+CD11b+F4/80+ and CD206+) polarization and promoting a suppressive molecular phenotype (IL4Rα +). These findings were functionally recapitulated, with quinolinate-induced M2 macrophages demonstrating potent inhibition of CD8+T-cell proliferation. Intriguingly, quinolinate also skewed M1 polarization towards an “M2-like” phenotype both molecularly (CD45+CD11b+F4/80+CD206+) and functionally, by inhibiting CD8+T-cell proliferation and decreasing phagocytosis efficiency. Targeting quinolinate’s upstream enzyme kynurenine-3-monooxygenase (KMO) inhibited M2 polarization in vitro and deceased M2 macrophage levels in vivo by 60%. This was unique to KMO, as targeting tryptophan metabolism by inhibiting the more established, upstream target IDO1 did not influence M2 macrophage levels. As emerging studies suggest M2 macrophages play a central role in contributing towards the potent immunosuppressive microenvironment in glioblastoma, therapeutic strategies designed to target quinolinate metabolism may serve as a novel immuno-metabolic checkpoint with direct clinical implications in this malignancy.

253 Anti-TIGIT antibodies require enhanced FcγR co-engagement for optimal T and NK cell-dependent anti-tumor immunity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A275-A275
Author(s):  
Rebecca Ward ◽  
Elena Paltrinieri ◽  
Marilyn Marques ◽  
Priyadarshini Iyer ◽  
Sylvia Dietrich ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Immunity ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Control ◽  
Tumor Bearing ◽  
Anti Tumor Activity ◽  
Ct26 Tumor ◽  
Dependent Mechanism

BackgroundT-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an important negative regulator of the immune response to cancer that contributes to resistance/relapse to anti-PD-1 therapy.1 In clinical trials, anti-human (h) TIGIT antibodies have shown promising activity in combination with anti-PD-1/PD-L1 antibodies for the treatment of various solid tumors.2 However, the optimal format for anti-TIGIT antibodies remains controversial. Here we describe a novel Fcγ receptor (FcγR)-dependent mechanism of action that is critical for enhancing T and NK cell anti-tumor immunity, and, further informs on the optimal design of anti-TIGIT antibodies.MethodsWe investigated a panel of Fc-silent, Fc-competent, and Fc-engineered anti-mouse (m) TIGIT antibody variants in syngeneic murine CT26 tumor-bearing or B16F10 pseudo-metastases models. To further elucidate the relative contribution of T and NK cells in controlling tumor growth, we assessed the activity of Fc-engineered anti-TIGIT antibodies in NK cell-depleted or T cell-deficient (Nu-Foxn1nu) CT26 tumor-bearing mice. Immune-related pharmacodynamic changes in the tumor microenvironment were assessed by flow cytometry. We further validated these findings in primary human T and NK cell activation assays using Fc-engineered anti-human TIGIT antibodies.ResultsThe Fc-engineered anti-mTIGIT antibody, which demonstrates enhanced binding to mouse FcγRIV, was the only variant to deliver single agent anti-tumor activity. The Fc-enhanced variant outperformed the Fc-competent variant while the Fc-inert variant had no anti-tumor activity. Tumor control by anti-mTIGIT antibodies was not dependent on Treg depletion, but rather on increased frequency of CD8+ T cells and activated NK cells (Ki67, IFNγ, CD107a and TRAIL) in the tumor microenvironment. Concordant with observations in the mouse, Fc-engineered anti-hTIGIT antibodies with improved binding to FcγRIIIA demonstrate superior T and NK cell activation in PBMC-based assays compared to a standard hIgG1 variant. Notably, superior activity of the Fc-engineered anti-hTIGIT antibody was observed from PBMC donors that express either high or low affinity FcγRIIIA. Blockade of FcγRIIIA or depletion of CD14+ and CD56+ cells reduced the functional activity of the Fc-enhanced anti-TIGIT antibody, confirming the requirement for FcγR co-engagement to maximize T cell responses.ConclusionsOur data demonstrate the importance of FcγR co-engagement by anti-TIGIT antibodies to promote immune activation and tumor control. First generation anti-TIGIT antibodies are not optimally designed to co-engage all FcγRIIIA variants. However, Fc-enhanced anti-TIGIT antibodies unlock a novel FcγR-dependent mechanism of action to enhance T and NK cell-dependent anti-tumor immunity and further improve therapeutic outcomes.ReferencesJohnston RJ, et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26:923–37.Rodriguez-Abreu D, et al., Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). Journal of Clinical Oncology 2020; 38:15_suppl, 9503–9503.

scholarly journals Lymphocyte subset analysis to evaluate the prognosis of HIV-negative patients with pneumocystis pneumonia

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fan Jin ◽  
Jing Xie ◽  
Huan-ling Wang
Keyword(s):  
T Cell ◽  
Cell Count ◽  
Lymphocyte Subsets ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Pneumocystis Pneumonia ◽  
Lymphocyte Subset ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
Hiv Negative

Abstract Objectives We analysed the peripheral blood lymphocyte subsets of human immunodeficiency virus (HIV)-negative patients infected with pneumocystis pneumonia (PCP) to determine the relationships between the levels of different types of lymphocytes and the prognosis of patients. Methods We retrospectively reviewed HIV-negative patients with PCP diagnosed in our department. All the eligible patients underwent lymphocyte subset analysis on admission. Results A total of 88 HIV-negative PCP patients were enrolled in the study. In univariate analyses, low CD4+ T cell count, low CD8+ T cell count, and low natural killer cell (NK cell) count were associated with higher in-hospital mortality. CD8+ T cell count ≤300/μL was found to be an independent risk factor for poor prognosis in multivariate logistical regression analysis (p = 0.015, OR = 11.526, 95% CI = 1.597–83.158). Although low CD4+ T cell and NK cell counts were not independent risk factors, the mortality rates of PCP patients decreased as the CD4+ T cell and NK cell counts increased. Conclusion The immune process of Pneumocystis jirovecii infection is complex but important. We propose that lymphocyte subsets could give clinicians a better understanding of patient immune status, helping with the early identification of potentially lethal infections and treatment decision making, such as adjusting the immunosuppressive regimen and choosing an appropriate patient monitoring level.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

Abstract NG04: Disrupting enhancers within the core epigenetic program of exhaustion improves CD8+ T cell responses and enhances tumor control

2021 ◽  
Author(s):  
Debattama Sen ◽  
Sarah A. Weiss ◽  
Brian C. Miller ◽  
Kathleen B. Yates ◽  
Martin W. Lafleur ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Tumor Control ◽  
Cell Responses ◽  
The Core

scholarly journals 584 Powerful synergistic effects of a STING agonist and the IL-2 superkine, H9, in eliciting NK and T cell responses against MHC I- and MHC I+ tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A614-A614
Author(s):  
Natalie Wolf ◽  
Cristina Blaj ◽  
Lora Picton ◽  
Gail Snyder ◽  
Li Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Combination Therapy ◽  
Nk Cells ◽  
Nk Cell ◽  
Tumor Regression ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Mhc I ◽  
Therapy Regimen ◽  
Cell Responses

BackgroundMost current cancer immunotherapies are based on mobilizing CD8 T cell responses. However, many types of tumors evade CD8 T cell recognition by displaying few or no antigens, or losing expression of MHC I. These considerations underlie the need for complementary therapies that mobilize other antitumor effector cells, such as NK cells, which preferentially kill MHC I-deficient cells. Cyclic dinucleotides (CDNs) activate the cGAS-STING pathway of the innate immune system and are candidates as immunotherapy agents. Intratumoral CDN injections induce type I IFNs and other mediators that amplify the CD8 T cell response and induce tumor regression [1]. CDN therapy also induces long-term tumor regressions in some MHC I-deficient tumor models, mediated primarily by NK cells [2].MethodsTo extend the efficacy of CDN therapy, we combined the IL-2 superkine, H9, or half-life extended H9, with CDNs to target and activate NK cells in the tumor microenvironment and prevent or delay the onset of NK cell desensitization [3,4]. In these studies, we utilized B16-F10 and MC38 tumor cells lacking B2m to examine effects of the combination therapy on MHC I-deficient tumor growth as well as to examine the activation of NK cells by flow cytometry and cytotoxicity assays. We also utilized B16-F10 WT and the spontaneous tumor model, MCA, to assess the effect of the combination therapy on MHC I+ tumors.ResultsHere we show that H9 synergized with CDN therapy to mobilize much more powerful antitumor responses against MHC I-deficient tumors than CDN alone. The responses were mediated by NK cells and in some cases CD4 T cells, and were accompanied by increased recruitment to and sustained activation of NK cells in the tumor. This combination therapy regimen activated NK cells systemically, as shown by antitumor effects distant from the site of CDN injection and enhanced cytolytic activity of splenic NK cells against tumor cell targets ex vivo. Finally, the same combination therapy regimen synergistically mobilized powerful CD8 T cell responses in the case of MHC I+ tumor cells, suggesting the generality of the approach. The approach was effective against primary sarcomas, as well, especially when combined with checkpoint therapy, leading to tumor regressions and long-term survival of many mice with MCA-induced sarcoma.ConclusionsOverall, our work demonstrates the impact of a novel combination therapy in mobilizing powerful NK and T cell-mediated antitumor activity, providing important justification for evaluating this approach for treating cancers that are refractory to available treatment options.ReferencesCorrales, L., Glickman, L.H., McWhirter, S.M., Kanne, D.B., Sivick, K.E., Katibah, G.E., Woo, S.R., Lemmens, E., Banda, T., Leong, J.J., et al. (2015). Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep 11, 1018–1030.Nicolai, C.J., Wolf, N., Chang, I.C., Kirn, G., Marcus, A., Ndubaku, C.O., McWhirter, S.M., and Raulet, D.H. (2020). NK cells mediate clearance of CD8(+) T cell-resistant tumors in response to STING agonists. Science immunology 5, eaaz2738.Levin, A.M., Bates, D.L., Ring, A.M., Krieg, C., Lin, J.T., Su, L., Moraga, I., Raeber, M.E., Bowman, G.R., Novick, P., et al. (2012). Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature 484, 529–533.Ardolino, M., Azimi, C.S., Iannello, A., Trevino, T.N., Horan, L., Zhang, L., Deng, W., Ring, A.M., Fischer, S., Garcia, K.C., and Raulet, D.H. (2014). Cytokine therapy reverses NK cell anergy in MHC-deficient tumors. J Clin Invest 124, 4781–4794.

scholarly journals 668 Lipid-instructed metabolic rewiring unleash the anti-tumor potential of CD8+ T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A696-A696
Author(s):  
Teresa Manzo ◽  
Carina Nava Lauveson ◽  
Teresa Maria Frasconi ◽  
Silvia Tiberti ◽  
Ignazio Caruana ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mitochondrial Function ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Metabolic Reprogramming ◽  
Tumor Control ◽  
Metabolic Fitness

BackgroundAdoptive cell therapy (ACT) harnesses the immune system to recognise tumor cells and carry out an anti-tumor function. However, metabolic constraints imposed by the tumour microenvironment (TME) suppress anti-tumor responses of CTL by reshaping their metabolism and epigenetic landscape. We have recently demonstrated that progressive accumulation of specific long-chain fatty acids (LCFAs) impair mitochondrial function and drives CD8+ T cell dysfunction. In this scenario, maintaining T cells in a less-differentiated state and with high metabolic plasticity during ex vivo T cell production and after infusion may have a strong therapeutic impact. Here, we propose a novel strategy to boost ACT efficacy by implementing T cell long-term functionality, metabolic fitness and preventing exhaustion through lipid-induced mitochondrial rewiring.MethodsWe screen different LCFAs and assess their ability to shape CD8+ T cell differentiation using multi-parametric flow cytometry, proliferation and cytotoxic assays, together with a complete transcriptomic and epigenomic profiling. Metabolic reprogramming of lipid-treated CD8+ T cell was examined by bioenergetic flux measurements paired with metabolomic and lipidomic analysis. Finally, the anti-tumor responses of lipid-instructed CD8 T cells was evaluated in a melanoma mouse model, known to poorly respond to immunotherapy.ResultsLCFAs-treated CD8+ T cells are endowed with highly effector and cytotoxic features but still retaining a memory-like phenotype with decreased PD1 protein levels. Consistently, analysis of the bioenergetic profile and mitochondrial activity has shown that LCFA-instructed CD8+ T cells display a greater mitochondrial fitness. Thus, in vitro LCFA-instructed CD8+ T cells are characterized by higher mitochondrial fitness, potent functionality, memory-like phenotype and PD-1 down-regulation, overall evoking the ideal T cell population associated with a productive anti-tumor response. The therapeutic potential of CD8 T cells lipid-induced metabolic rewiring was further confirmed in vivo. ACT performed with LCFA-reprogrammed CD8 T cells induces higher frequency of memory T cells, which show high polyfunctionality and mitochondrial function, decreased PD1 expression, ultimately resulting in improved tumor control. In addition, LCFA-induced metabolic rewiring during manufacturing of human CAR-redirected T cells, generated a CD8+ T cell memory-like population with higher mitochondrial fitness coupled with a much potent cytotoxic activity.ConclusionsThese results suggest that LCFAs dictate the fate of CD8+ T cell differentiation and could be considered as a molecular switch to fine-tune memory T cell formation and metabolic fitness maintenance, linking lipid metabolism to anti-tumor surveillance. This will be of fundamental importance for a new generation of adoptive T cell-based therapies.Ethics ApprovalThe experiments described were performed in accordance with the European Union Guideline on Animal Experiments and mouse protocols were approved by Italian Ministry of Health and the IEO Committee.

scholarly journals Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5856
Author(s):  
Myung-Chul Kim ◽  
Zeng Jin ◽  
Ryan Kolb ◽  
Nicholas Borcherding ◽  
Jonathan Alexander Chatzkel ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Single Cell Analysis ◽  
Clear Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Cellular Mechanisms ◽  
T Cell Infiltration ◽  
Immunological Mechanisms

Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.

scholarly journals Establishment and Validation of a Genetic Label Associated With M2 Macrophage Infiltration to Predict Survival in Colon Cancer Patients and Assist Immunotherapy

2021 ◽  
Author(s):  
Boyang Xu ◽  
Ziqi Peng ◽  
Guanyu Yan ◽  
Ningning Wang ◽  
Moye Chen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Microsatellite Instability ◽  
Cancer Patients ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
High Morbidity ◽  
M2 Macrophages ◽  
Hub Genes

Abstract Background: Colon cancer is a kind of malignant tumor with high morbidity and mortality. Researchers have tried to interpret it from different perspectives and divide it into different subtypes in order to achieve individualized treatment. With the rise of immunotherapy, its value in the field of tumor has initially emerged. Based on the above background, from the perspective of immune infiltration, this study classified colon cancer according to the infiltration of M2 macrophages in patients with colon cancer and further explored it.Methods: Cibersort was used to analyze the level of immune cell infiltration in colon cancer patients in the TCGA database. WGCNA, Consensus Clustering analysis, Lasso analysis, and univariate KM analysis were used to screen and verify the hub genes associated with M2 macrophages. PCA was used to establish the M2 macrophage-related score—M2I Score. The correlation between M2I Score and somatic cell variation and microsatellite instability were analysed. Furthermore the correlation between M2 macrophage score and differences in immunotherapy sensitivity was also explored. Results: M2 macrophage infiltration was associated with poor prognosis. Four hub genes (ANKS4B, CTSD, TIMP1, and ZNF703) were selected as the progression-related genes associated with M2 macrophages. A stable and accurate M2I Score for M2 macrophages used in COAD was constructed based on four hub genes. M2I Score was positively correlated with tumor mutation load (TMB). The M2I Score of MSI-H group was higher than that of MSI-L group and MSS group. Combine with the TCIA database, we concluded that patients with a high M2I Score were more sensitive to PD-1 inhibitors and PD-1 inhibitors combined with CTLA-4 inhibitors. The low rating group may have better efficacy without immune checkpoint inhibitors or with CTLA4 inhibitors alone.Conclusion: Four prognostic hub genes associated with M2 macrophages were screened to establish the M2I Score and divided the patients into two subgroups: high M2I Score group and low M2I Score group. TMB, microsatellite instability and sensitivity to immunotherapy were higher in the high-rated group. PD-1 inhibitors or PD-1 combined with CTLA-4 inhibitors are preferred for patients in the high-rated group who are more sensitive to immunotherapy.

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