Immune complexity of epithelial cancers

Pr Alejandra Martinez et Dr Anna Salvioni

The aim of this line of research is to decipher the immune regulatory mechanisms that limit the anti-tumour potential of antigen-specific T cells and modify immune checkpoints (ICPs) and T cell exhaustion. Three types of epithelial tumours, those of the ovary, the uterine cervix and the ENT sphere (head and neck), which are known to be immunogenic but remain poorly or not at all sensitive to immunotherapy with PD-1/PD-L1 inhibitors, are our priority pathologies (DECIdE protocol, DEcipher Cancer ImmunogEnicity, NCT03958240).

The concept of T-cell depletion has evolved in recent years. These cells are no longer considered to be depleted per se. Rather, it is an adaptation of the immune response to chronic infections and cancers with IBO-expressing lymphocytes having an epigenetic programme that allows them to persist despite chronic stimulation. As these lymphocytes are the main target of ICH inhibitors (IPCI), we studied the depletion of T cells infiltrating ovarian, cervical and head and neck tumours. We showed that tumour-infiltrating CD8 and CD4 T cells reach a so-called terminal exhaustion stage but remain sensitive to anti-PD-1 drugs that allow them to express their effector potential. Circulating T cells specific to tumour antigens are in an early stage of exhaustion and proliferate under the effect of anti-PD-1, thus potentially reaching the tumour site. In a cohort of patients with ENT tumours treated with PD-1/PD-L1 axis blocking IPCI, we have shown that terminal depleted CD8 T cells at the tumour site were predictive of patient survival and response to immunotherapy.

Our ongoing studies aim to understand :

• The mechanisms governing the development of an antigen-specific T cell response and the acquisition of the depleted phenotype, depending on target antigen families and oncogenesis mechanisms, such as homologous recombination deficiency (HRD) status in ovarian cancer and oncogenic virus (HPV) dependent mechanisms
• The role of tumour antigen-specific depleted T cells in cervical cancer progression (predictive value of disease extension).

Technologies used:

Flow cytometry (17 colour staining); HLA/peptide multimer analysis of antigen-specific T cells; T cell functional analyses; RNASeq, single-cell RNAseq; CITE-Seq; dCODE Dextramer® guided single-cell RNASeq; Bioinformatics analysis; Multiplex immunohistochemistry.