scholarly journals Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review

2020 ◽  
Vol 9 (6) ◽  
pp. 1741 ◽  
Author(s):  
Lena Bohaumilitzky ◽  
Magnus von Knebel Doeberitz ◽  
Matthias Kloor ◽  
Aysel Ahadova
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Mismatch Repair ◽  
Science Studies ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Dna Mismatch ◽  
T Cell Infiltration ◽  
Hereditary Tumors ◽  
Mmr Deficiency

Microsatellite instability (MSI) represents one of the major types of genomic instability in human cancers and is most common in colorectal cancer (CRC) and endometrial cancer (EC). MSI develops as a consequence of DNA mismatch repair (MMR) deficiency, which can occur sporadically or in the context of Lynch syndrome (LS), the most common inherited tumor syndrome. MMR deficiency triggers the accumulation of high numbers of somatic mutations in the affected cells, mostly indel mutations at microsatellite sequences. MSI tumors are among the most immunogenic human tumors and are often characterized by pronounced local immune responses. However, so far, little is known about immunological differences between sporadic and hereditary MSI tumors. Therefore, a systematic literature search was conducted to comprehensively collect data on the differences in local T cell infiltration and immune evasion mechanisms between sporadic and LS-associated MSI tumors. The vast majority of collected studies were focusing on CRC and EC. Generally, more pronounced T cell infiltration and a higher frequency of B2M mutations were reported for LS-associated compared to sporadic MSI tumors. In addition, phenotypic features associated with enhanced lymphocyte recruitment were reported to be specifically associated with hereditary MSI CRCs. The quantitative and qualitative differences clearly indicate a distinct biology of sporadic and hereditary MSI tumors. Clinically, these findings underline the need for differentiating sporadic and hereditary tumors in basic science studies and clinical trials, including trials evaluating immune checkpoint blockade therapy in MSI tumors.

scholarly journals Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity

2021 ◽  
Author(s):  
Tyler Jacks ◽  
Peter Westcott ◽  
Francesc Muyas ◽  
Olivia Smith ◽  
Haley Hauck ◽  
...  
Keyword(s):  
T Cell ◽  
Mismatch Repair ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Mismatch Repair Deficiency ◽  
Dna Mismatch ◽  
T Cell Infiltration ◽  
Repair Deficiency ◽  
Tumor Mutational Burden

Abstract DNA mismatch repair deficiency (MMRd) is associated with high tumor mutational burden (TMB), increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy1. Nevertheless, about half of MMRd tumors do not respond to ICB for unclear reasons. While cell line transplant models of MMRd have reinforced the importance of TMB in immune response2,3, critical questions remain regarding the role of immunosurveillance in the evolution of MMRd tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with ablation of MMR via in vivo CRISPR/Cas9 targeting. Surprisingly, MMRd in these models did not increase T cell infiltration or response to ICB. Mechanistically, we showed this lack of immunogenicity to be driven by profound intratumoral heterogeneity. Studies in immune deficient animals further demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating heterogeneity. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.

Mismatch repair deficiency in cholangiocarcinoma.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 269-269 ◽  
Author(s):  
Paul Raymond Kunk ◽  
Joseph Mounir Obeid ◽  
Kevin Winters ◽  
Patcharin Pramoonjago ◽  
Dirk G. Brockstedt ◽  
...  
Keyword(s):  
T Cell ◽  
Mismatch Repair ◽  
Immune Cell ◽  
Tissue Microarrays ◽  
High Rate ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Mmr Deficiency ◽  
Unmet Treatment Need ◽  
Mesothelin Expression

269 Background: Cholangiocarcinoma (CC) is a fatal malignancy with an unmet treatment need. With the approval of immunotherapy for solid tumors with mismatch repair (MMR) deficiency, there is a renewed interest in MMR testing. Little is known about the incidence of MMR deficiency in CC or its correlation to survival, immune cell infiltration, PD-L1 and other proteins expressed in CC such as mesothelin. Methods: CC tumors were identified from patients treated at the University of Virginia from 2000-2014. Tissue microarrays (TMAs) were constructed of 3-4 cores from each tumor and were stained by immunohistochemistry for MMR genes (MLH1, PMS2, MSH2, MSH6), mesothelin, PD-L1 and immune cells. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. Correlation with overall survival was assessed using log-rank tests and classification and regression trees, with p values < 0.05 considered significant. Results: Ninety-one tumors were analyzed: 24 intrahepatic, 33 hilar, and 34 distal. MMR deficiency was found in 20 tumors (22%). None of the MMR deficient tumors co-expressed PD-L1 (>1%), which was found in 15% of the remaining tumors. T cell infiltration (CD4, CD8 and FoxP3) did not differ between MMR deficient or proficient tumors. Patients with MMR deficiency had a trend towards worse survival compared to those with proficiency (median OS: 19.2 vs. 28.1 months, p = 0.07). MMR deficient tumors showed a lower mesothelin expression compared to MMR proficient tumors, median 8 vs. 129 positive cells per TMA (p = 0.08). Patients with MMR deficiency and low mesothelin expression had a worse outcome compared to patients with MMR proficiency and high mesothelin expression (median OS: 14.5 vs. 30.0 months, p = 0.05). Conclusions: Given the high rate of MMR deficiency, all CC tumors should be tested and may benefit from anti-PD-1 therapy. The poor prognosis of MMR deficient CC may be independent of T-cell infiltration and additional studies are needed to better characterize the genetic and molecular landscape of this subset of tumors.

scholarly journals Effects of PD-1 blockade on ovarian follicles in a prepubertal female mouse

2021 ◽  
Author(s):  
Pauline C. Xu ◽  
Yi Luan ◽  
Seok-yeong Yu ◽  
Jing Xu ◽  
Donald W. Coulter ◽  
...  
Keyword(s):  
T Cell ◽  
Pediatric Patients ◽  
Ovarian Follicles ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Chimeric Antibody ◽  
Published Data ◽  
Antibody Treatment ◽  
Primordial Follicles ◽  
T Cell Infiltration

Immunotherapy has emerged at the forefront of cancer treatment. Checkpoint inhibitor pembrolizumab (KEYTRUDA), a chimeric antibody which targets programmed cell death protein 1 (PD-1), has been approved by the FDA for use in pediatric patients with relapsed or refractory classical Hodgkin’s lymphoma. However, there is currently no published data regarding the effects of pembrolizumab on the ovary of female pediatric patients. In this study, prepubertal immunocompetent and immunodeficient female mice were injected with pembrolizumab or anti-mouse PD-1 antibody. The number of primordial follicles significantly decreased post-injection of both pembrolizumab and anti-mouse PD-1 antibody in immunocompetent mice. However, no changes in follicle numbers were observed in immunodeficient nude mice. Superovulation test and vaginal opening experiments suggest that there is no difference in the number of COCs and the timing of puberty onset between the control and anti-mouse PD-1 antibody treatment groups, indicating that there is no effect on short-term fertility. Elevation of pro-inflammatory cytokine TNF-α following COX-2 upregulation was observed in the ovary. CD3+ T-cell infiltration was detected within some ovarian follicles and between stromal cells of the ovaries in mice following treatment with anti-mouse PD-1 antibody. Thus, PD-1 immune checkpoint blockade affects the ovarian reserve through a mechanism possibly involving inflammation following CD3+ T-cell infiltration.

scholarly journals B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiayu Wang ◽  
Hongya Wu ◽  
Yanjun Chen ◽  
Jinghan Zhu ◽  
Linqing Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Inverse Correlation ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
T Cell Infiltration

AbstractNegative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8+ T-cell infiltration in CRC tissues. Kaplan−Meier analysis showed that patients with high B7-H5 expression and low CD8+ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8+ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8+ T cells. Importantly, the depletion of CD8+ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

scholarly journals IMMU-11. DUAL TARGETING OF IL-6 AND CD40 OVERCOMES GLIOBLASTOMA RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii107-ii107
Author(s):  
Fan Yang ◽  
Steven Brem ◽  
Yi Fan
Keyword(s):  
T Cell ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
Genetic Ablation ◽  
T Cell Infiltration ◽  
Dual Targeting ◽  
Animal Survival ◽  
Cd40 Expression

Abstract Glioblastoma (GBM) is refractory to current T cell-based immunotherapies such as checkpoint blockade. GBM is characterized by extensive infiltration of immunosuppressive macrophages (Mφs) that contribute to the treatment resistance. Here we develop a dual-targeting strategy to synergistically activate tumor-associated Mφs, which overcomes GBM resistance to therapeutic blockade of the PD1 and CTLA4 checkpoints. Consistent with a previously established role of IL-6 in alternative Mφ polarization, we show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T cell infiltration and enhances animal survival in a genetically engineered mouse GBM model. However, IL-6 inhibition does not synergize PD-1 and CTLA-4 blockade in GBM. Interestingly, we reveal that anti-IL-6 therapy reduces CD40 expression in GBM-associated Mφs. Our transcriptome analysis identifies a Stat3/HIF-1a-mediated axis, through which IL-6 regulates CD40 expression in Mφs. Finally, we show that combination of IL-6 blockade with CD40 stimulation robustly reverses Mφ-mediated tumor immunosuppression, enhances T cell infiltration, and sensitizes GBM to PD-1 and CTLA-4 blockade treatment, cumulating in inhibited tumor growth and extended animal survival. These findings illustrate a cellular mechanism that regulates Mφ-mediated tumor immunity, and suggest that dual-targeting IL-6 and CD40 may offer exciting opportunities for improving immunotherapy against GBM.

scholarly journals Improved Immunotherapy Efficacy by Vascular Modulation

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5207
Author(s):  
Emma L. Newport ◽  
Ana Rita Pedrosa ◽  
Alexandra Njegic ◽  
Kairbaan M. Hodivala-Dilke ◽  
José M. Muñoz-Félix
Keyword(s):  
T Cell ◽  
Cancer Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Cell Therapies ◽  
T Cell Infiltration ◽  
Tumour Oxygenation

Several strategies have been developed to modulate the tumour vasculature for cancer therapy including anti-angiogenesis and vascular normalisation. Vasculature modulation results in changes to the tumour microenvironment including oxygenation and immune cell infiltration, therefore lending itself to combination with cancer therapy. The development of immunotherapies has led to significant improvements in cancer treatment. Particularly promising are immune checkpoint blockade and CAR T cell therapies, which use antibodies against negative regulators of T cell activation and T cells reprogrammed to better target tumour antigens, respectively. However, while immunotherapy is successful in some patients, including those with advanced or metastatic cancers, only a subset of patients respond. Therefore, better predictors of patient response and methods to overcome resistance warrant investigation. Poor, or periphery-limited, T cell infiltration in the tumour is associated with poor responses to immunotherapy. Given that (1) lymphocyte recruitment requires leucocyte–endothelial cell adhesion and (2) the vasculature controls tumour oxygenation and plays a pivotal role in T cell infiltration and activation, vessel targeting strategies including anti-angiogenesis and vascular normalisation in combination with immunotherapy are providing possible new strategies to enhance therapy. Here, we review the progress of vessel modulation in enhancing immunotherapy efficacy.

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