Innate Immune Recognition of Cancer

Abstract

The observation that a subset of cancer patients show evidence for spontaneous CD8+ T cell priming against tumor-associated antigens has generated renewed interest in the innate immune pathways that might serve as a bridge to an adaptive immune response to tumors. Manipulation of this endogenous T cell response with therapeutic intent-for example, using blocking antibodies inhibiting PD-1/PD-L1 (programmed death-1/programmed death ligand 1) interactions-is showing impressive clinical results. As such, understanding the innate immune mechanisms that enable this T cell response has important clinical relevance. Defined innate immune interactions in the cancer context include recognition by innate cell populations (NK cells, NKT cells, and γδ T cells) and also by dendritic cells and macrophages in response to damage-associated molecular patterns (DAMPs). Recent evidence has indicated that the major DAMP driving host antitumor immune responses is tumor-derived DNA, sensed by the stimulator of interferon gene (STING) pathway and driving type I IFN production. A deeper knowledge of the clinically relevant innate immune pathways involved in the recognition of tumors is leading toward new therapeutic strategies for cancer treatment.

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

“…The presence of spontaneous TILs correlates with better prognosis, especially for tumor immunotherapies (Woo et al, 2015). Recently, consistent with our observations, two exceptional studies have shown that both mouse and human tumor cells can program to suppress chemokine productions that can limit immune infiltrates leading to resistance to Tang et al Page 9 Cancer Cell.…”

Tumor vaccines with dsRNA adjuvant ARNAX induces antigen-specific tumor shrinkage without cytokinemia

“…The adjuvant directs the DC-priming host immune system to respond to the appropriate target: generating mature DC for tumor eradication. 9 We show in this report that a TLR3-specific adjuvant preferentially induces TAA-specific CTL as well as NK cell activation without provoking inflammation or systemic cytokinemia. 8 Immunotherapy with antibodies against PD-L1 or PD-1 has brought cancer patients hope of a positive outcome: in patients with an inoperable solid tumor, more than 20% diminished without severe side-effects.…”

“…EG7 (OVA), B16 (survivin) and C1498 (WT1) were found to be good systems in C57BL/6 mice, and we mainly used the EG7 (OVA)-implant system, since OVA is a multi-epitope antigen and CTL activation is represented by SL8-tetramer. 8,9 OT-1 proliferation, tetramer assay and IFNg production were employed to measure CTL production. Therapeutic response was monitored by tumor shrinkage, and parallelism was checked by monitoring cytokine levels in serum, NK cell and TAA-specific CTL activation.…”

Natural killer cell mediated immunosurveillance of pediatric neuroblastoma

“…Nonetheless, there has been growing awareness over the last decade that innate immune responses, including those mediated by NK cells, play a major role in immunosurveillance against some tumor types, especially at the level of metastatic dissemination. 1 This chronological sequence (T before NK cells) most likely does not indicate a hierarchy of importance between T and NK lymphocytes, but rather reflects three interrelated facts, namely, (i) a relatively poor knowledge on the physiology of NK cells (as compared to T lymphocytes), (ii) the existence of major species differences between mouse and human NK cells, and (iii) the absence of standardized tools for the functional exploration of human NK cells. 2 On theoretical grounds, anticancer immunosurveillance may occur in two specific situations.…”