Immune-Checkpoint Blockade Opposes CD8+ T-cell Suppression in Human and Murine Cancer

Abstract

Immune-checkpoint blockade enhances antitumor responses against cancers. One cancer type that is sensitive to checkpoint blockade is squamous cell carcinoma of the head and neck (SCCHN), which we use here to study limitations of this treatment modality. We observed that CD8 þ tumor-infiltrating lymphocytes (TILs) in SCCHN and melanoma express excess immune checkpoints components PD-1 and Tim-3 and are also CD27 À /CD28 À , a phenotype we previously associated with immune dysfunction and suppression. In ex vivo experiments, patients' CD8 þ TILs with this phenotype suppressed proliferation of autologous peripheral blood T cells. Similar phenotype and function of TILs was observed in the TC-1 mouse tumor model. Treatment of TC-1 tumors with anti-PD-1 or anti-Tim-3 slowed tumor growth in vivo and reversed the suppressive function of multi-checkpoint þ CD8 þ TIL. Similarly, treatment of both human and mouse PD-1 þ Tim-3 þ CD8 þ TILs with anticheckpoint antibodies ex vivo reversed their suppressive function. These suppressive CD8 þ TILs from mice and humans expressed ligands for PD-1 and Tim-3 and exerted their suppressive function via IL10 and close contact. To model therapeutic strategies, we combined anti-PD-1 blockade with IL7 cytokine therapy or with transfer of antigen-specific T cells. Both strategies resulted in synergistic antitumor effects and reduced suppressor cell function. These findings enhance our understanding of checkpoint blockade in cancer treatment and identify strategies to promote synergistic activities in the context of other immunotherapies.

Novel treatments using PD1 inhibitors for advanced and metastatic cutaneous squamous cell carcinoma

“…Some types of tumors can induce some suppressive changes in CD8 + T cells losing anti-tumor functions like loss of CD27 and CD28 [23,24]. These PD1+ CD8 + T cells suppress the proliferative capacity of normal autologous T cells.…”

“…These PD1+ CD8 + T cells suppress the proliferative capacity of normal autologous T cells. PD1 inhibitors slow the tumor growth through retrieving normal cytotoxic CD8 + T cell functions [23]. There are studies that showed antitumor immunity capacity can also be increased by IL7 treatment which protect T cells from phenotypic alterations and loss of CD27 and CD28 [24].…”

“…There are studies that showed antitumor immunity capacity can also be increased by IL7 treatment which protect T cells from phenotypic alterations and loss of CD27 and CD28 [24]. The PD1 inhibitor and IL7 cytokine combinative therapy in vivo is reported to synergize the antitumor effects of PD1 inhibitors [23].…”

Transcriptomic Features of T Cell-Barren Tumors Are Conserved Across Diverse Tumor Types

“…T cell infiltration associated with good prognosis is often accompanied by the presence of other activated proinflammatory cells [e.g., T H 1 T cells, natural killer (NK) cells, and antigen-presenting cells (APCs)] indicative of a T cellinflamed phenotype that has also been associated with a positive response to immune checkpoint blockade (ICB) (3)(4)(5)(6). Moreover, an increase in CD8+ T cell tumor infiltration induced by ICB is associated with durable treatment response in both patients and animal models (7)(8)(9). Thus, the establishment and maintenance of an immunologically hot TME, characterized by abundant effector T cell infiltration, is clinically desirable.…”

Modulation of the Gut Microbiota Alters the Tumor-Suppressive Efficacy of Tim-3 Pathway Blockade in a Bacterial Species- and Host Factor-Dependent Manner

“…Blocking Tim-3 signaling decreases tumor growth in mouse models [12,13]. Furthermore, concomitant blockade of Tim-3 and PD-1 pathways enhances tumor suppression better than blocking either pathway alone [2,[14][15][16]. Several mechanisms are believed to underlie the tumor-suppressive effect of Tim-3 blockade, such as decrease in regulatory T cell frequencies, functional restoration of tumor-in ltrated T cells, increased dendritic cell recruitment to the tumor tissue, and enhanced NK cell activity [7,13,[16][17][18][19].…”