BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

Haymaker, Cara; Wu, Richard C.; Ritthipichai, Krit; Bernatchez, Chantale; Forget, Marie Andrée; Chen, Jie Qing; Liu, Hui; Wang, Ena; Marincola, Francesco M.; Hwu, Patrick; Radvanyi, Laszlo G.

doi:10.1080/2162402x.2015.1014246

Cited by 53 publications

(48 citation statements)

References 48 publications

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“…Our previous report demonstrated that CD8 + BTLA + human TIL produce more IL-2 upon activation (14). Thus, we further investigated whether BTLA signaling could be responsible for IL-2 secretion.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously demonstrated that the CD8 + BTLA + TIL subset had an improved proliferative capacity in response to IL-2 (14). Thus, we sought to determine whether BTLA signaling motifs could play a role in T cell proliferation.…”

Section: Resultsmentioning

confidence: 99%

“…Our recent work demonstrated that CD8 + BTLA + TIL exhibited the molecular signature of less-differentiated T cells as compared to their CD8 + BTLA − counterpart and had increased persistence following adoptive transfer in treated patients (14). Several studies in both immunodeficient murine and non-human primate models also demonstrated that central memory derived effector CD8 + T cells established a pool of in vivo persistent memory T cells (15–18).…”

Section: Introductionmentioning

confidence: 99%

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Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter

Ritthipichai

Haymaker

Martinez

et al. 2017

Clinical Cancer Research

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Purpose Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40–50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte attenuator) expression on transferred CD8+ TIL was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8+BTLA+TIL subset and define the contribution of the Grb2 motif of BTLA in T cell co-stimulation. Experimental Design We determined the functional role and downstream signal of BTLA in both human CD8+ TIL and mouse CD8+ T cells. Functional assays were used including single cell analysis, Reverse Phase Protein Array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as Patient-Derived Xenograft (PDX) model using Immunodeficient NOD-scid IL2Rgammanull (NSG) tumor-bearing mice treated with autologous TIL. Results CD8+BTLA− TIL could not control tumor growth in vivo as well as their BTLA+ counterpart and antigen-specific CD8+BTLA− T cells had impaired recall response to a vaccine. However CD8+BTLA+ TIL displayed improved survival following the killing of a tumor target and heightened “serial killing” capacity. Using mutants of BTLA signaling motifs we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. Conclusions Our data portrays BTLA as a molecule with the singular ability to provide both co-stimulatory and co-inhibitory signals to activated CD8+ T cells, resulting in extended survival, improved tumor control and the development of a functional recall response.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter

Ritthipichai

Haymaker

Martinez

et al. 2017

Clinical Cancer Research

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“…In the spleen however, there were significant increases in the frequencies of both CTLA-4 + and TIM-3 + cells in both the CD4 + and CD8 + compartments with combination treatment (Figure 2C). B and T Lymphocyte Attenuator (BTLA) is another inhibitory marker initially expressed on activated T cells, but subsequent downregulation (BTLA − ) is associated with terminal T cell differentiation in the tumor and a decreased capacity to proliferate (34). With combination treatment, BTLA + T cells were significantly decreased in both the CD4 + and CD8 + T cell populations of the spleen (Figure 2D, 2E).…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, we noted a significant decrease in the frequency of BTLA + peripheral T cells after concurrent combination treatment. Others have suggested that BTLA − cells are less effective in the tumor, with reduced proliferative capacity and decreased responsiveness to costimulatory molecules (34). We also observed reduced proliferation in concurrent combination-treated T cells in the tumor seven days after the conclusion of treatment (Figure 5A, 5B), despite an increase in proliferation six days prior (Figure 3D).…”

Section: Discussionmentioning

confidence: 99%

Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40

Messenheimer

Jensen

Afentoulis

et al. 2017

Clinical Cancer Research

267

183

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Purpose Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to impact patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T cell costimulatory receptors such as OX40 remains a critical question. Experimental Design We utilized an anti-PD-1 refractory, orthotopically-transplanted MMTV-PyMT mammary cancer model to investigate the anti-tumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. Since PD-1 naturally aids in immune contraction after T cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 followed by anti-PD-1. Results The concurrent addition of anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type 1 and type 2 serum cytokines and significantly augmented expression of inhibitory receptors or exhaustion markers CTLA-4 and TIM-3 on T cells. Combination treatment increased intratumoral CD4+ T cell proliferation at day 13, but at day 19 both CD4+ and CD8+ T cell proliferation was significantly reduced compared to untreated mice. In two tumor models, sequential combination of anti-OX40 followed by anti-PD-1 (but not the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV-PyMT tumors sequential combination was dependent on both CD4+ and CD8+ T cells and completely regressed tumors in ~30% of treated animals. Conclusions These results highlight the importance of timing for optimized therapeutic effect with combination immunotherapies and suggest the testing of sequencing in combination immunotherapy clinical trials.

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Mining the Complex Family of Protein Tyrosine Phosphatases for Checkpoint Regulators in Immunity

Penafuerte

Perez-Quintero

Vinette

et al. 2017

Current Topics in Microbiology and Immunology

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The family of protein tyrosine phosphatases (PTPs) includes 107 genes in humans that are diverse in their structures and expression profiles. The majority are present in immune cells and play various roles in either inhibiting or promoting the duration and amplitude of signaling cascades. Several PTPs, including TC-PTP (PTPN2) and SHP-1 (PTPN6), have been recognized as being crucial for maintaining proper immune response and self-tolerance, and have gained recognition as true immune system checkpoint modulators. This chapter details the most recent literature on PTPs and immunity by examining their known functions in regulating signaling from either established checkpoint inhibitors or by their intrinsic properties, as modulators of the immune response. Notably, we review PTP regulatory properties in macrophages, antigen-presenting dendritic cells, and T cells. Overall, we present the PTP gene family as a remarkable source of novel checkpoint inhibitors wherein lies a great number of new targets for immunotherapies.

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BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

Abstract: (2015) BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties, OncoImmunology, 4:8, e1014246,

Cited by 53 publications

References 48 publications

Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter

Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter

Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40

Mining the Complex Family of Protein Tyrosine Phosphatases for Checkpoint Regulators in Immunity

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