In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors

Khalil, Danny N.; Suek, Nathan; Campesato, Luís Felipe; Budhu, Sadna; Redmond, David; Samstein, Robert M.; Krishna, Chirag; Panageas, Katherine S.; Capanu, Marinela; Houghton, Sean; Hirschhorn, Daniel; Zappasodi, Roberta; Giese, Rachel; Gasmi, Billel; Schneider, Michael; Gupta, Aditi; Harding, James J.; Moral, John A.; Balachandran, Vinod P.; Wolchok, Jedd D.; Merghoub, Taha

doi:10.1172/jci128562

Cited by 35 publications

(26 citation statements)

References 53 publications

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“…To examine the relationship between antitumor efficacy of neoantigen vaccination and the generation of neoantigen-specific CX3CR1+CD8+ T cells, we sought to validate a preclinical model of neoantigen vaccination using MC38 colon adenocarcinoma cells that harbor a singleepitope mutation within the Adpgk protein (Supplemental Figure 1) (18). In this model, to maximize the therapeutic efficacy of neoantigen vaccination with mutant Adpgk peptide (AdpgkMut), dual TLR/CD40 stimulation was used as vaccine adjuvants ( Figure 1A), which has been known to synergistically activate DCs, augment CD8+ T cell expansion, and mediate potent antitumor immunity in multiple preclinical models (19)(20)(21)(22). Vaccination of AdpgkMut, but not irrelevant AH1 peptide with agonistic anti-CD40 antibody (Ab), and TLR3 agonist, poly(I:C) (referred to as AdpgkMut/TLR3/CD40 hereafter) markedly delayed the growth of established MC38 tumors and improved survival ( Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺CD8⁺T cells in mice

Yamauchi

Hoki

Oba

et al. 2020

Preprint

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Running title: CX3CR1 as a circulating biomarker for vaccine therapy 33 34 Word counts (excluding abstract and references): 2,476 35 36 Abstract 38Background The use of tumor mutation-derived neoantigen represents a promising approach for 39 cancer vaccines. Preclinical and early-phase human clinical studies have shown the successful 40 induction of tumor neoepitope-directed responses; however, overall clinical efficacy of 41 neoantigen vaccines has been limited. One major limitation of this strategy is the lack of a 42 reliable blood-based surrogate marker for clinical response. Here, we investigated a role of 43 CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation in predicting response 44 to neoantigen vaccination in a preclinical model. 45Methods Mice bearing MC38 colon adenocarcinoma cells that harbor a single-epitope mutation 46 within the Adpgk protein were treated with mutant Adpgk peptide (AdpgkMut) in combination 47 with toll-like receptor 3 (TLR3) agonist poly(I:C) and/or anti-CD40 antibody (Ab). Antitumor 48 efficacy of neoantigen vaccination and the frequency of peripheral blood AdpgkMut-specific 49 CX3CR1+CD8+ T cells were assessed. Mechanisms underlying the generation of CX3CR1+CD8+ 50 T cells were examined using knockout and bone marrow chimeric mice. 51 ResultsWe found that CD40 stimulation significantly enhanced antitumor efficacy of 52 neoantigen and TLR3 agonist vaccination, which was associated with an increased frequency of 53 circulating AdpgkMut-specific effector CX3CR1+CD8+ T cells. Generation of neoantigen-specific 54 CX3CR1+CD8+ T cells by AdpgkMut/CD40/TLR3 stimulation was dependent on CD40 and Batf3 55 in bone marrow-derived cells. Further mechanistic studies using mixed bone marrow chimeras 56identified key roles for CD40 and CD80/86, but not CD70 signaling in Batf3-dependent 57 conventional type 1 dendritic cells (cDC1s) for generation of neoantigen-specific cytotoxic 58 CX3CR1+CD8+ T cells and therapeutic efficacy of neoantigen vaccine. 59Conclusions Taken together, our results underscore critical roles of cDC1s and an implication of 60 dual CD40/TLR3 stimulation in neoantigen-based therapeutic vaccines, and demonstrate the 61 potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine clinical trials. 62 63

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Section: Resultsmentioning

confidence: 99%

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺CD8⁺T cells in mice

Yamauchi

Hoki

Oba

et al. 2020

Preprint

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“…Due to the exhaustion of antitumor T cells, the number of T cells interacting with tumor antigens is diminished, limiting the efficacy of PD-1 blockade [ 195 ]. In order to overcome T-cell exhaustion, intratumoral in situ injection using dual CD40-TLR4 stimulation was applied and exhausted Tc cells were eliminated in murine models with bilateral tumor approach to assess its efficacy both on the treated tumor and on the distant tumor which improved tumor control with the addition of PD-1 inhibitor [ 196 ]. Activation of the CD40 receptors by tumor cells is an important step for T-cell immunity.…”

Section: Immunotherapy In Pancreatic Ductal Adenocarcinoma-currentmentioning

confidence: 99%

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Saka

Gökalp

Piyade

et al. 2020

Cancers

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T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

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“…A growing body of evidence shows that engagement of CD40 on DCs provides potent maturation and anti-apoptotic signals to DCs, augments priming of antigen-specific cytotoxic T lymphocytes (CTLs), induces interleukin 12 (IL-12) production for the development of T helper 1 (Th1) cells, and overcomes peripheral T cell tolerance 19 , 20 . Combined TLR/CD40 stimulation synergistically enhances CD8 + T cell expansion 21 , and mediates potent antitumor immunity in multiple syngeneic mouse models 22 – 24 .…”

Section: Introductionmentioning

confidence: 99%

Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s

et al. 2020

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The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+ Slamf6+ CD8+ T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.

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In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors

Cited by 35 publications

References 53 publications

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺CD8⁺T cells in mice

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺CD8⁺T cells in mice

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s

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In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors

Cited by 35 publications

References 53 publications

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+CD8+T cells in mice

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+CD8+T cells in mice

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s

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CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺CD8⁺T cells in mice

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺CD8⁺T cells in mice