Although immune-based therapy is proving to be a success in several cancer types, only a set of patients appear to respond to immune checkpoint blockade including PD-1 and CTLA-4. A better understanding of the crucial components of cancer immunity is therefore necessary. T lymphocytes, a key element, are found within the tumor microenvironment and seem to be critical in determining the efficacy of immune surveillance. In this review, we will depict the pro-and antitumor roles of major T cell subsets in distinct cancer tissues. The central role of the mainly antitumor subsets, cytotoxic T cells and Th1 cells, will be delineated. Subsequently, we will indicate how other subsets including Th2, Th17, and T regulatory cells exhibit ambivalent roles. We will also describe the emerging and favorable role of Th9 cells in cancer immunity. In parallel, we will go through main mechanisms by which these cells operate, and will pinpoint pathways, which could be used as potential therapeutic targets in order to positively impact the immune response and ameliorate patients' clinical outcome.

BackgroundGlioma is the most common type of primary brain tumor in adults. Patients with the most malignant form have an overall survival time of <16 months. Although considerable progress has been made in defining the adapted therapeutic strategies, measures to counteract tumor escape have not kept pace, due to the developed resistance of malignant glioma. In fact, identifying the nature and role of distinct tumor-infiltrating immune cells in glioma patients would decipher potential mechanisms behind therapy failure.MethodsWe integrated into our study glioma transcriptomic datasets from the Cancer Genome Atlas (TCGA) cohort (154 GBM and 516 LGG patients). LM22 immune signature was built using CIBERSORT. Hierarchical clustering and UMAP dimensional reduction algorithms were applied to identify clusters among glioma patients either in an unsupervised or supervised way. Furthermore, differential gene expression (DGE) has been performed to unravel the top expressed genes among the identified clusters. Besides, we used the least absolute shrinkage and selection operator (LASSO) and Cox regression algorithm to set up the most valuable prognostic factor.ResultsOur study revealed, following gene enrichment analysis, the presence of two distinct groups of patients. The first group, defined as cluster 1, was characterized by the presence of immune cells known to exert efficient antitumoral immune response and was associated with better patient survival, whereas the second group, cluster 2, which exhibited a poor survival, was enriched with cells and molecules, known to set an immunosuppressive pro-tumoral microenvironment. Interestingly, we revealed that gene expression signatures were also consistent with each immune cluster function. A strong presence of activated NK cells was revealed in cluster 1. In contrast, potent immunosuppressive components such as regulatory T cells, neutrophils, and M0/M1/M2 macrophages were detected in cluster 2, where, in addition, inhibitory immune checkpoints, such as PD-1, CTLA-4, and TIM-3, were also significantly upregulated. Finally, Cox regression analysis further corroborated that tumor-infiltrating cells from cluster 2 exerted a significant impact on patient prognosis.ConclusionOur work brings to light the tight implication of immune components on glioma patient prognosis. This would contribute to potentially developing better immune-based therapeutic approaches.

Malignant melanoma is a major public health issue displaying frequent resistance to targeted therapy and immunotherapy. A major challenge is to better understand how melanoma cells evade immune elimination and how tumor growth and metastasis is facilitated by tumor microenvironment. Here, we show that expression of the cytokine TSLP by epidermal keratinocytes is induced by cutaneous melanoma in both mice and humans. Using genetically engineered models of melanoma and tumor cell grafting combined with TSLP knockout or overexpression, we defined a crosstalk between melanoma cells, keratinocytes and immune cells in establishing a tumor promoting microenvironment. Keratinocyte-derived TSLP is induced by signal(s) derived from melanoma cells and subsequently acts via immune cells to promote melanoma progression and metastasis. Furthermore, we show that TSLP signals through TSLPR-expressing dendritic cells to play an unrecognized role in promoting GATA3 + Tregs expressing a gene signature including ST2, CCR8, ICOS, PD-1, CTLA-4 and OX40 and exhibiting a potent suppressive activity on CD8 + T cell proliferation and IFNγ production. An analogous population of GATA3-expressing Tregs was also identified in human melanoma tumors. Together, our study provides novel insights into the role of TSLP in programming a pro-tumoral immune microenvironment in cutaneous melanoma.

Tumor-infiltrating Tregs (TITR) constitute a sub-family of immuno-suppressive cells abundantly found in multiple solid cancers. They play a critical role in tumor progression and their specific depletion has been recently propose as a novel therapeutic strategy to fight cancers. Based on the transcriptional analysis of tumor infiltrating immune cells, the G-protein coupled receptor CCR8 was found to be expressed on murine and human TITR, but not on proinflammatory effector T cells. The CCR8 receptor therefore represents a unique TITR target for the development of novel depletive antibody-based therapeutics. At Domain Therapeutics, a diverse library of several dozens of mouse mAbs directed against the hCCR8 was discovered and characterized, providing a unique source for the development of a best-in-class and well differentiated anti-hCCR8 depleting antibody for the treatment of cancers.Special attention was paid on two important characteristics for the selection of our depleting mAb candidates: (1) their ability to detect all CCR8 positive immunosuppressive cells and (2) the combination of different killing modes of action (ADCC, ADCP, CDC) to trigger an optimal depletion.Our selected mAb candidates were nominated based on their capacity to bind to immunosuppressive cells present in different tumor tissues and optimal depleting activity. The impact of our mAbs on tumor growth and on the immune tumor microenvironment (TME) were also studied in mouse hCCR8-KI mice. Finally, following a comprehensive in vitro benchmarking mAb analysis, we identified key differentiating points versus competitor’s mAbs. Nominated candidates wil be ready to enter cell line generation efforts in early 2023. Citation Format: Iseulys Richert, Malaury Schappler, Alice Gentil Dit Maurin, Megane Jeannelle, Solene Rose, Pauline Urquia, Dounia Chraa, Luc Baron, Maria Dolores Garcia Fernandez, Quentin Ruet, Camille Dietsch, Orphee Blanchard, Safia Ayachi, Christel Franchet, Alexandre Fontayne, Claudine Vermot-Desroches, Stephan Schann, Nathalie Lenne. Depleting hCCR8 mAb Therapy #2: Selection of candidates for the development of innovative depleting anti CCR8 therapeutic antibodies to control the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2945.