scholarly journals Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence

2021 ◽  
Vol 12 ◽  
Author(s):  
Phuong T. Le ◽  
Ngoc Ha ◽  
Ngan K. Tran ◽  
Andrew G. Newman ◽  
Katharine M. Esselen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transcription Initiation ◽  
Transcriptional Activity ◽  
Immune Checkpoint Blockade ◽  
Effector T Cells ◽  
Effector Cells ◽  
Cell Based Therapy ◽  
Therapy Target ◽  
And Control

Immune checkpoint blockade (ICB) relieves CD8+ T-cell exhaustion in most mutated tumors, and TCF-1 is implicated in converting progenitor exhausted cells to functional effector cells. However, identifying mechanisms that can prevent functional senescence and potentiate CD8+ T-cell persistence for ICB non-responsive and resistant tumors remains elusive. We demonstrate that targeting Cbx3/HP1γ in CD8+ T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity at Lef1 and Il21r. LEF-1 and IL-21R are necessary for Cbx3/HP1γ-deficient CD8+ effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence of Cbx3/HP1γ-deficient CD8+ T cells facilitates remodeling of the tumor chemokine/receptor landscape ensuring their optimal invasion at the expense of CD4+ Tregs. Thus, CD8+ T cells heightened effector function consequent to Cbx3/HP1γ deficiency may be distinct from functional reactivation by ICB, implicating Cbx3/HP1γ as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumors.

scholarly journals Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence

2021 ◽  
Author(s):  
To-Ha Thai ◽  
Phuong Le ◽  
Ngoc Ha ◽  
Ngan Tran ◽  
Andrew Newman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Transcription Initiation ◽  
Cd8 T Cell ◽  
Checkpoint Blockade ◽  
Cell Based Therapy ◽  
Functional Exhaustion ◽  
Clinical Models ◽  
Therapy Target

Abstract Checkpoint blockade can reverse CD8+ T-cell functional exhaustion, and TCF-1 is essential for this process. However, identifying mechanisms that can prevent functional senescence and potentiate CD8+ T-cell persistence in checkpoint blockade non-responsive tumors remains a challenge. We demonstrate that targeting Cbx3/HP1γ causes augmented transcription initiation, chromatin remodeling at Lef1 and Il21r leading to increased transcriptional activity at these loci. Mechanistic studies show LEF-1 and IL-21R are required for Cbx3/HP1γ-deficient CD8+ effector T cells to persist resulting in improved control of ovarian cancer, melanoma and neuroblastoma in pre-clinical models. Cbx3/HP1γ-deficient CD8+ T cells enhanced persistence in the TME facilitates remodeling of the chemokine/receptor landscape that ensures their optimal tumor invasion at the expense of CD4+ Tregs. Thus, CD8+ T cells heightened effector function consequent to Cbx3/HP1γ deficiency may be distinct from functional reactivation by checkpoint blockade, implicating Cbx3/HP1γ as a viable cancer T-cell-based therapy target for resistant, non-responsive solid tumors.

Engraftment Fitness of Human Central Memory-Derived Effector CD8+ T Cells In Immunodeficient Mice

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1019-1019
Author(s):  
Xiuli Wang ◽  
Berger Carolina ◽  
Stanley R. Riddell ◽  
ChingLam W Wong ◽  
Stephen Forman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Tumor Response ◽  
Memory T Cells ◽  
Effector T Cells ◽  
Caspase Activity ◽  
Effector Cells ◽  
Nog Mice

Abstract Abstract 1019 Development of T cell products that have engineered specificity for CD19 has broad application to adoptive transfer therapy for B-lineage lymphoma and leukemia. Clinical studies have demonstrated the safety and feasibility of T cell transfer as a therapy for patients. But the potency of this strategy has proven challenging, primarily due to issues relating to a lack of persistence of the adoptively transferred cells in patients. The repertoire of memory T cells is heterogeneous with respect to phenotypic, functional, and epigenetic attributes. Memory T cells are divided into sub-populations of 1) effector memory (TEM) cells that distribute to tissue beds and exhibit immediate cytolytic effector functioning, and 2) central memory (TCM) cells that home to lymph nodes based on CD62L/CCR7 expression and are capable of extensive proliferative activity upon re-encountering antigen. Thus the cell-intrinsic programming of distinct memory T cell subtypes, such as TEM and TCM, likely dictate divergent fates of their derived effector cells. To address this important issue, a clear functional dichotomy between TCM- and TEM-derived CD8+ CTLs was recently delineated in a nonhuman primate model, where it was found that virus-specific CD8+ CTL clones derived from TCM, but not TEM precursors, establish persistent and functional memory following adoptive transfer. Here, we extended these studies to human effector T cells using CMV as antigen model system to investigate the engraftment of human CMVpp65-specific CD8+ effector T cells derived in vitro from either sort purified CD45RO+CD62L+ TCM or CD45RO+CD62L- TEM precursors in NOD/Scid IL-2RγCnull (NOG) mice. TCM-derived effector cells (TE(CM)) and TEM-derived effector cells (TE(EM)) were adoptively transferred (i.v) into NOG mice reconstituted with human IL-15 and T cell levels in circulation were evaluated at different time points by FACS. 20% CD8+ TE(CM) and 3% CD8+ TE(EM) were detected on day 14. Then after, engraftment of the CD8+ TE(CM) remained at a steady state of approx 2% of circulating mononuclear cells for 100 days while TE(EM) remained at or below the level of detection, indicating that TE(CM) were superior in their ability to engraft in response to IL-15 as compared to TE(EM) after adoptive transfer (P<0.05). The long-term (100 days) persisting CD8+ TE(CM), harvested from primary recipient mice were found to be capable of engrafting secondary recipients. TcR Vβ analysis of persisting cells demonstrated that CD8+ TE(CM) engraftment was polyclonal, suggesting that homeostatic engraftment fitness is a general feature of these cells. To delineate the mechanism(s) by which TE(CM) exhibit superior in vivo engraftment, TE(CM) and TE(EM) were first labeled with CFSE before in vivo administration. CFSE profiles appear that the TE(EM) proliferated more extensively than TE(CM) early after adoptive transfer as indicated by the percent of cells which diluted CFSE on day 9 (i.e., 80% vs. only 25%, respectively). However, using D2R cleavage as a measure of caspase activity as a surrogate for apoptosis, 5.8% of engrafting TE(CM) were positive for activated caspase activity compared to 31.6% of TE(EM), suggesting that in NOG mice both CD8+ TE(CM) and TE(EM) proliferate in response to IL-15 whereas TE(CM) are intrinsically resistant to caspase activation and apoptosis. We also evaluated the antigen specific responsiveness of engrafted cells. Weekly infusions of irradiated pp65+/A2+ LCL as antigen significantly augmented the levels of circulating CD8+ TE(CM) as compared to no antigen stimulation (P<0.05), whereas CD8+ TE(EM) did not respond to antigen challenge. Moreover, when CMVpp65 specific CD8+ TE(CM) or TE(EM) were infused into CMVpp65+ tumor bearing mice, tumor cells progressed in mice receiving TE(EM) at a rate similar to untreated control mice over a ten day observation period, whereas TE(CM) significantly controlled tumor progression (P<0.05), indicating that CD8+ TE(CM) but not TE(EM) are able to mediate an anti-tumor response. Together these studies confirm that human CD8+ effector T cells derived from TCM precursors are capable of persistence after infusion, can proliferate in in vivo in response to antigen, can mediate an anti-viral or anti tumor response, and are likely the preferred T cells for antigen specific anti-tumor adoptive T cell therapy . Disclosures: No relevant conflicts of interest to declare.

scholarly journals Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 1888-1898 ◽  
Author(s):  
Xiuli Wang ◽  
Carolina Berger ◽  
ChingLam W. Wong ◽  
Stephen J. Forman ◽  
Stanley R. Riddell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector T Cells ◽  
Central Memory ◽  
Model Systems ◽  
Adoptive T Cell Therapy ◽  
Effector Memory ◽  
T Cell Therapy ◽  
Effector Cells

Abstract In clinical trials of adoptive T-cell therapy, the persistence of transferred cells correlates with therapeutic efficacy. However, properties of human T cells that enable their persistence in vivo are poorly understood, and model systems that enable investigation of the fate of human effector T cells (TE) have not been described. Here, we analyzed the engraftment of adoptively transferred human cytomegalovirus pp65-specific CD8+ TE cells derived from purified CD45RO+CD62L+ central memory (TCM) or CD45RO+CD62L− effector memory (TEM) precursors in an immunodeficient mouse model. The engraftment of TCM-derived effector cells (TCM/E) was dependent on human interleukin-15, and superior in magnitude and duration to TEM-derived effector cells (TEM/E). T-cell receptor Vβ analysis of persisting cells demonstrated that CD8+ TCM/E engraftment was polyclonal, suggesting that the ability to engraft is a general feature of TCM/E. CD8+ TEM/E proliferated extensively after transfer but underwent rapid apoptosis. In contrast, TCM/E were less prone to apoptosis and established a persistent reservoir of functional T cells in vivo characterized by higher CD28 expression. These studies predict that human CD8+ effector T cells derived from TCM precursors may be preferred for adoptive therapy based on superior engraftment fitness.

Do CD8 effector cells need IL-7R expression to become resting memory cells?

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 1949-1956 ◽  
Author(s):  
Eva Buentke ◽  
Anne Mathiot ◽  
Mauro Tolaini ◽  
James Di Santo ◽  
Rose Zamoyska ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Half Life ◽  
Effector T Cells ◽  
Memory Cells ◽  
Effector Cells ◽  
Physiological Conditions ◽  
Transgenic Model

Abstract The role for IL-7R expression in the differentiation of effector T cells into resting memory remains controversial. Here, using a conditional IL-7R transgenic model, we were able to test directly whether CD8 effector T cells require IL-7R expression for their differentiation into resting memory cells. In the absence of IL-7R expression, effector cells transferred into “full” hosts underwent a protracted and unremitting contraction compared with IL-7R–expressing control cells and were unable to develop into long-term resting memory cells. Surprisingly, when the same effector cells were transferred into empty T-cell–deficient hosts, they could generate long-lived fully functional resting memory cells independently of IL-7R expression. Formation of these latter cells was found to be dependent on IL-15, because the same IL-7R–deficient effector cells were rapidly lost from IL-15–deficient hosts, having a half-life of less than 40 hours. Therefore, our data suggest that, under physiological conditions, both IL-7 and IL-15 synergize to promote the formation of memory cells directly by limiting the contraction of effectors that occurs following an immune response and that reexpression of IL-7R is a key checkpoint in the regulation of this process.

scholarly journals Inosine is an alternative carbon supply that supports effector T cell proliferation and antitumor function under glucose restriction

2019 ◽  
Author(s):  
Tingting Wang ◽  
JN Rashida Gnanaprakasam ◽  
Xuyong Chen ◽  
Siwen Kang ◽  
Xuequn Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adaptive Immune System ◽  
Immune Checkpoint Blockade ◽  
Effector T Cells ◽  
Immune Functions ◽  
Carbon Supply ◽  
Wide Range ◽  
Robust Adaptive

AbstractT cells undergo a characteristic metabolic rewiring that fulfills the dramatically increased bioenergetic, biosynthetic, and redox demands following antigen stimulation. A robust adaptive immune system requires effector T cells to respond and adapt to fluctuations in environmental nutrient levels imposed by infectious and inflammatory sites in different tissues. Inevitably, such responsiveness and adaptation reflect metabolic plasticity, allowing T cells to elicit immune functions by using a wide range of nutrient substrates. Here, we show that effector T cells utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase (PNP). Using Stable Isotope-Resolved Metabolomics (SIRM), we demonstrated that ribose moiety of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors. Accordingly, the dependence of T cells on extracellular glucose for growth and effector functions can be relieved by inosine. On the other hand, cancer cells display diverse capacity to utilize inosine as a carbon resource. Moreover, the supplement of inosine enhances the anti-tumor efficacy of immune-checkpoint blockade or adoptive T cell transfer, reflecting the capability of inosine in relieving tumor-imposed metabolic restrictions on T cells in vivo.

scholarly journals Distinct migratory pattern of naive and effector T cells through the blood–CSF barrier following Echovirus 30 infection

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Marie Wiatr ◽  
Carolin Stump-Guthier ◽  
Daniela Latorre ◽  
Stefanie Uhlig ◽  
Christel Weiss ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Choroid Plexus Papilloma ◽  
Effector T Cells ◽  
Cell Phenotype ◽  
Migration Process ◽  
Effector Cells ◽  
Echovirus 30 ◽  
Basolateral Side

Abstract Background Echovirus 30 (E-30) is one of the most frequently isolated pathogens in aseptic meningitis worldwide. To gain access to the central nervous system (CNS), E-30 and immune cells have to cross one of the two main barriers of the CNS, the epithelial blood–cerebrospinal fluid barrier (BCSFB) or the endothelial blood–brain barrier (BBB). In an in vitro model of the BCSFB, it has been shown that E-30 can infect human immortalized brain choroid plexus papilloma (HIBCPP) cells. Methods In this study we investigated the migration of different T cell subpopulations, naive and effector T cells, through HIBCPP cells during E-30 infection. Effects of E-30 infection and the migration process were evaluated via immunofluorescence and flow cytometry analysis, as well as transepithelial resistance and dextran flux measurement. Results Th1 effector cells and enterovirus-specific effector T cells migrated through HIBCPP cells more efficiently than naive CD4+ T cells following E-30 infection of HIBCPP cells. Among the different naive T cell populations, CD8+ T cells crossed the E-30-infected HIBCPP cell layer in a significantly higher number than CD4+ T cells. A large amount of effector T cells also remained attached to the basolateral side of the HIBCPP cells compared with naive T cells. Analysis of HIBCPP barrier function showed significant alteration after E-30 infection and trans- as well as paracellular migration of T cells independent of the respective subpopulation. Morphologic analysis of migrating T cells revealed that a polarized phenotype was induced by the chemokine CXCL12, but reversed to a round phenotype after E-30 infection. Further characterization of migrating Th1 effector cells revealed a downregulation of surface adhesion proteins such as LFA-1 PSGL-1, CD44, and CD49d. Conclusion Taken together these results suggest that naive CD8+ and Th1 effector cells are highly efficient to migrate through the BCSFB in an inflammatory environment. The T cell phenotype is modified during the migration process through HIBCPP cells.

scholarly journals γδ T Cells from Tolerized αβ T Cell Receptor (TCR)–deficient Mice Inhibit Contact Sensitivity-Effector T Cells In Vivo, and Their Interferon-γ Production In Vitro

1996 ◽  
Vol 184 (6) ◽  
pp. 2129-2140 ◽  
Author(s):  
Marian Szczepanik ◽  
Laurel R. Anderson ◽  
Hiroko Ushio ◽  
Wlodzimierz Ptak ◽  
Michael J. Owen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Γδ T Cells ◽  
Interferon Γ ◽  
Effector T Cells ◽  
High Dose ◽  
Effector Cells

Contact sensitivity (CS) responses to reactive hapten Ag, such as picryl chloride (PCl) or oxazolone (OX), are classical examples of T cell–mediated immune responses in vivo that are clearly subject to multifaceted regulation. There is abundant evidence that downregulation of CS may be mediated by T cells exposed to high doses of Ag. This is termed high dose Ag tolerance. To clarify the T cell types that effect CS responses and mediate their downregulation, we have undertaken studies of CS in mice congenitally deficient in specific subsets of lymphocytes. The first such studies, using αβ T cell–deficient (TCRα−/−) mice, are presented here. The results clearly show that TCRα−/− mice cannot mount CS, implicating αβ T cells as the critical CS-effector cells. However, TCRα−/− mice can, after high dose tolerance, downregulate α+/+ CS-effector T cells adoptively transferred into them. By mixing ex vivo and then adoptive cell transfers in vivo, the active downregulatory cells in tolerized α−/− mice are shown to include γδ TCR+ cells that also can downregulate interferon-γ production by the targeted CS-effector cells in vitro. Downregulation by γδ cells showed specificity for hapten, but was not restricted by the MHC. Together, these findings establish that γδ T cells cannot fulfill CS-effector functions performed by αβ T cells, but may fulfill an Ag-specific downregulatory role that may be directly comparable to reports of Ag-specific downregulation of IgE antibody responses by γδ T cells. Comparisons are likewise considered with downregulation by γδ T cells occurring in immune responses to pathogens, tumors, and allografts, and in systemic autoimmunity.

scholarly journals Immune Suppression in CLL Is Mediated By the L-Amino Acid Oxidase IL4I1, a Reason for the Treatment Failure of IDO1 Inhibitors

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Selcen Öztürk ◽  
Murat Iskar ◽  
Murat Sunbul ◽  
Philipp M Rößner ◽  
Marc Zapatka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Suppression ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
Tumor Development ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Effector T Cells ◽  
Chimeric Mice

A better understanding of cancer-induced immune suppression has led to the development of novel immunotherapy approaches, some of which are considered as breakthrough in cancer treatment. One of the promising targets that was followed in clinical trials is indoleamine-2,3-dioxygenase 1 (IDO1) which is a tryptophan (Trp)-catabolizing enzyme that produces metabolites such as kynurenine (Kyn) which promote immune evasion by suppressing T cell activity, and therefore tumor progression. Enhanced expression of IDO1 was described for patients with B cell lymphoma, including chronic lymphocytic leukemia (CLL), and we observed a strong upregulation of IDO1 and a significantly increased Kyn to Trp serum ratio in the Eµ-TCL1 mouse model of CLL. To evaluate the therapeutic potential of this pathway in CLL, we treated Eµ-TCL1 mice with the IDO1 inhibitors 1-Methyl-D-tryptophan or Epacadostat. Both drugs led to initial treatment responses, but failed to improve tumor development over time which is in line with disappointing results of a first phase III clinical trial combining Epacadostat with immune checkpoint blockade for patients with melanoma. In search for an explanation for this failure, we investigated genes that are induced upon resistance to immune checkpoint blockade and identified the phenylalanine-catabolizing enzyme interleukin-4-induced 1 (IL4I1). IL4I1 is strongly expressed in cancer-associated myeloid cells as well as tumor cells of different entities, including CLL and other B cell lymphoma, and was attributed immunosuppressive functions. We thus explored its role in cancer immune escape in bone marrow-chimeric mice that lack IL4I1 in the hematopoietic tumor microenvironment. Adoptive transfer of Eµ-TCL1 leukemia in these mice showed that lack of IL4I1 in hematopoietic cells resulted in a dramatically reduced tumor development compared to respective control mice (Figure 1A). In-depth analysis of the immune compartment of these mice by flow cytometry and transcriptome analyses revealed that IL4I1 deficiency was associated with lower expression of immune checkpoint molecules including PD-1 on CD8 T cells. Moreover, CD8+ effector T cells of IL4I1-deficient mice were highly enriched in a transcriptional signature of genes that was downregulated upon T-cell exhaustion (Figure 1B). We further observed less suppressive regulatory T cells, and enhanced antigen presentation capacity of dendritic cells in the IL4I1-deficient chimeric mice developing CLL. Altogether, these results provide evidence for a central role for IL4I1 in CLL-associated immune suppression and suggest IL4I1 as attractive novel target for immunotherapy of cancer, including tumors that do not respond to IDO1 inhibitors. Figure 1: CLL development and CD8 T cell phenotype in mice with IL4I1-deficient microenvironment A: Bone marrow (BM)-chimeric mice were generated by i.v. transplantation of 5 x 106 BM cells of wildtype (WT) or Il4i1-/-mice in lethally irradiated C57BL/6 mice. After reconstitution of the hematopoietic system, 10 weeks after BM transfer, mice were i.v. transplanted with 1 x 107 malignant B cells of Eµ-TCL1 mice and CLL development was monitored in peripheral blood over time by quantifying absolute number of CD5+ CD19+ CLL cells by flow cytometry. B: 5 weeks after CLL cell transfer, mice were sacrificed and splenic CD8+ effector T cells were sorted for transcriptome analysis by microarrays. Gene set enrichment analysis of ranked-list of genes (fold change) was performed using published signatures which showed an enrichment of genes that are downregulated in exhausted versus memory CD8+ T cells in Il4i1-/- in comparison to WT mice. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cheng-Tao Jiang ◽  
Kai-Ge Chen ◽  
An Liu ◽  
Hua Huang ◽  
Ya-Nan Fan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Noncovalent Interactions ◽  
Killer Cell ◽  
Antibody Immobilization ◽  
Effector Cells ◽  
Nanoparticle Surface

AbstractModulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.

scholarly journals Innate Immune Cells and Their Contribution to T-Cell-Based Immunotherapy

2020 ◽  
Vol 21 (12) ◽  
pp. 4441 ◽  
Author(s):  
Pierpaolo Ginefra ◽  
Girieca Lorusso ◽  
Nicola Vannini
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cells ◽  
Adoptive Cell Therapy ◽  
Adaptive Immune Response ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Innate Immune Cells

In recent years, immunotherapy has become the most promising therapy for a variety of cancer types. The development of immune checkpoint blockade (ICB) therapies, the adoptive transfer of tumor-specific T cells (adoptive cell therapy (ACT)) or the generation of T cells engineered with chimeric antigen receptors (CAR) have been successfully applied to elicit durable immunological responses in cancer patients. However, not all the patients respond to these therapies, leaving a consistent gap of therapeutic improvement that still needs to be filled. The innate immune components of the tumor microenvironment play a pivotal role in the activation and modulation of the adaptive immune response against the tumor. Indeed, several efforts are made to develop strategies aimed to harness innate immune cells in the context of cancer immunotherapy. In this review, we describe the contribution of innate immune cells in T-cell-based cancer immunotherapy and the therapeutic approaches implemented to broaden the efficacy of these therapies in cancer patients.

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