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Author(s): Jinfang Zhang [1]; Xia Bu [2]; Haizhen Wang [3]; Yasheng Zhu [4]; Yan Geng [3]; Naoe Taira Nihira [1]; Yuyong Tan [1, 5]; Yanpeng Ci [1, 6]; Fei Wu [...]

Author(s): Se Jin Im [1]; Masao Hashimoto [1]; Michael Y. Gerner [2, 3]; Junghwa Lee [1]; Haydn T. Kissick [1, 4]; Matheus C. Burger [5]; Qiang Shan [6]; J. Scott [...]

The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity (1-6), but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion (1,2,7). Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cell (s8,9). Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits--including durable responses--to patients with different malignancies (10-13). However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments., In this study, we used two distinct progresser 3-methylcholanthrene-induced (MCA) sarcoma cell lines (d42m1-T3 and F244) and asked whether they expressed sufficient immunogenicity to be controlled by checkpoint blockade immunotherapy. [...]

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25–CD122–CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.PD-1+TCF1+ stem-like CD8+ T cells—precursors of exhausted CD8+ T cells—are not fate-locked into the exhaustion program; their differentiation trajectory can be changed by IL-2 signals. [ABSTRACT FROM AUTHOR]

Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses (1-3). As such, immune modulatory therapies that enhance and/or restore the function of virus-specific immunity may protect from disease progression. Here we investigate the safety and immune restoration potential of blockade of the co-inhibitory receptor programmed death 1 (PD-1) (4,5) during chronic simian immunodeficiency virus (SIV) infection in macaques. We demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T-cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Blockade was effective during the early (week 10) as well as late (~week 90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for control of human immunodeficiency virus infections., Virus-specific T cells show varying degrees of functional impairment during chronic infections (6,7). Although these T cells retain some antiviral functions, they are less polyfunctional compared with antiviral T cells [...]

Author(s): Laurent Monney [1]; Catherine A. Sabatos [1]; Jason L. Gaglia [1]; Akemi Ryu [1]; Hanspeter Waldner [1]; Tatyana Chernova [2]; Stephen Manning [3]; Edward A. Greenfield [1, 2]; Anthony [...]

Author(s): Alexander J. McAdam [1]; Rebecca J. Greenwald [1]; Michele A. Levin [1]; Tatyana Chernova [2]; Nelly Malenkovich [2]; Vincent Ling [3]; Gordon J. Freeman [2, 4]; Arlene H. Sharpe [...]

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection 1 . Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1 + TCF1 + stem-like CD8 +  T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8 +  T cells that resemble highly functional effector CD8 +  T cells seen after an acute viral infection. The generation of these qualitatively superior CD8 + T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1 + TCF1 + stem-like CD8 + T cells, also referred to as precursors of exhausted CD8 + T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8 + T cells emerging from the stem-like CD8 + T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer 2,3 , and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)