Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown that inhibitory signals can be impaired, blocking T cell activation and function. MoAbs, used as both single-agents or in combination with standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC), have exhibited advantages in terms of overall survival and response rate; nivolumab, pembrolizumab, atezolizumab and more recently, durvalumab, have already been approved for lung cancer treatment and more compounds are in the pipeline. A better understanding of signaling elicited by these antibodies on T cell subsets, as well as identification of biological determinants of sensitivity, resistance and correlates of efficacy, will help to define the mechanisms of antitumor responses. In addition, the relevance of T regulatory cells (Treg) involved in immune responses in cancer is attracting increasing interest. A major challenge for future research is to understand why a durable response to immune checkpoint inhibitors (ICIs) occurs only in subsets of patients and the mechanisms of resistance after an initial response. This review will explore current understanding and future direction of research on ICI treatment in lung cancer and the impact of tumor immune microenvironment n influencing clinical responses.

Tissue-resident memory (Trm) cells are specialized components of both CD4+ and CD8+ T cell subsets that persist in peripheral nonlymphoid tissues following infections and provide fast response in case of a secondary invasion by the same pathogen. Trm cells express the surface markers CD69, CD103, and the immune checkpoint molecule PD-1. Trm cells develop not only in the context of infections but also in tumors, where they can provide a line of defense as suggested by the positive correlation between the frequency of tumor-infiltrating Trm cells and patients' survival. Trm cells persistence in peripheral tissues depends on their adaptation to the local microenvironment and the presence of survival factors, mainly IL-7, IL-15, and Notch ligands. However, the cell sources of these factors are largely unknown, especially in the context of tumors. Here, we show that head-neck squamous cell carcinoma (HNSCC) is enriched in CD4+ and CD8+ T cells with a Trm phenotype. Moreover, we show that mesenchymal stromal cells that accumulate in HNSCC are a source of survival factors and allow proper expression of Trm-typical markers in a VCAM1-dependent manner.

The immune response arises from a fine balance of cellular and molecular mechanisms that provide for surveillance, tolerance, and elimination of dangers as pathogens. Improving the quality of the immune response remains a major goal in immunotherapy and vaccine development. Sulfavant A (SULF A) is a sulfolipid that has shown promising adjuvant activity in a cancer vaccine model. Here we report that SULF A is the first synthetic small molecule binding to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2). The receptor engagement initiates an unconventional maturation of Dendritic cells (DCs) leading to upregulation of the Major Histocompatibility Complex class II (MHC Class II) and costimulatory molecules (CD83, CD86, DC54) without release of T helper type 1 (Th1) or 2 (Th2) cytokines. According to a TREM2 mechanism, this response is mediated by SYK-NFAT axis and is compromised by blockade and gene silencing of the receptor. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and induced interleukin-10 (IL-10) release after lipopolysaccharide (LPS) stimulation. These results well support the adjuvant effect of SULF A and offer novel insights into the role of TREM2 in the differentiation of an unprecedented DC phenotype (homeDCs) that contributes to the maintenance of immune homeostasis without compromising lymphocyte activation and immunogenic response. The biological function of SULF-A may be of interest in various physiological and pathological processes involving the immune system.

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