Immunology

Immunotherapy and the ovarian cancer microenvironment: Exploring potential strategies for enhanced treatment efficacy

AbstractDespite progress in cancer immunotherapy, ovarian cancer (OC) prognosis continues to be disappointing. Recent studies have shed light on how not just tumour cells, but also the complex tumour microenvironment, contribute to this unfavourable outcome of OC immunotherapy. The complexities of the immune microenvironment categorize OC as a ‘cold tumour’. Nonetheless, understanding the precise mechanisms through which the microenvironment influences the effectiveness of OC immunotherapy remains an ongoing scientific endeavour. This review primarily aims to dissect the inherent characteristics and behaviours of diverse cells within the immune microenvironment, along with an exploration into its reprogramming and metabolic changes. It is expected that these insights will elucidate the operational dynamics of the immune microenvironment in OC and lay a theoretical groundwork for improving the efficacy of immunotherapy in OC management.

Co‐Expression of Dominant‐Negative TGF‐β Receptor 2 Enhances the Therapeutic Efficacy of Novel TREM1/DAP12‐BB‐Based CAR‐T Cells in Solid Tumours

ABSTRACTChimeric antigen receptor (CAR) T‐cell therapy has exhibited remarkable efficacy in the treatment of haematological malignancies, yet its application in solid tumours is hindered by the immunosuppressive tumour microenvironment (TME). In this study, a novel SS1‐TREM1/DAP12‐BB CAR‐T cell was devised to target ovarian cancer and further engineered to co‐express the dominant‐negative TGF‐β receptor 2 (DNR) to combat CAR‐T cell exhaustion in TME. The incorporation of DNR effectively blocked TGF‐β signalling, thereby enhancing CAR‐T cell survival and antitumor activity in a TGF‐β1‐rich environment. In vivo evaluations demonstrated that DNR co‐expression potentiated the antitumor efficacy of TREM1/DAP12‐BB CAR‐T cells and conferred resilience against tumour rechallenge. These findings underscore the broad potential of DNR co‐expression in CAR design, presenting a novel therapeutic strategy for patients with recurrent ovarian cancer.

Targeting PI3Kα increases the efficacy of anti‐PD‐1 antibody in cervical cancer

AbstractTargeting programmed death 1(PD‐1) has been approved for relapsed cervical cancer with unsatisfactory clinical efficacy. This study aims to analyse the impact of PI3K pathway activation on tumour immune microenvironment and evaluates the immune sensitization effect by PI3K inhibition in cervical cancer. The effect of PIK3CA mutation on PD‐L1 expression and CD8+ T cells differentiation was determined in cervical cancer tissues. Luciferase and ChIP‐qPCR/PCR assays were used to determine the transcriptional regulation of PD‐L1 by PIK3CA‐E545K. The effects of PI3K inhibitor treatment on immune environment in vitro and in vivo were evaluated by RNA sequencing (RNA‐seq) and flow cytometry. The efficacy of PI3K inhibitor and anti‐PD‐1 therapy was assessed in cell‐derived xenografts (CDX) and patients‐derived xenografts (PDX). PD‐L1 overexpression is more frequently observed in elder women with squamous cervical carcinoma. It predicts longer progress‐free survival and overall survival. PIK3CA mutation results in increased mRNA and protein levels of PD‐L1, the repression of CD8+ T cell differentiation in cervical cancer. Here, we report a case that continuous pembrolizumab monotherapy treatment induced complete remission of a recurrent cervical cancer patient with systemic metastasis and PIK3CA‐E545K mutation, implying that PIK3CA mutation is potentially a biomarker for pembrolizumab treatment in cervical cancer. Specifically, this mutation promotes the expression of PD‐L1 by upregulating the transcription factor IRF1. PI3Kα‐specific inhibitor markedly activates immune microenvironment by regulating the PD‐1/L1‐related pathways and promoting CD8+ T cell differentiation and proliferation in Caski‐CDXs with PIK3CA‐E545K mutation. PI3Kα inhibitor significantly enhances the anti‐tumour efficacy of PD‐1 blockade in CDXs and PDXs. PIK3CA mutations may predict the response of cervical cancer to PD‐1 blockade. The efficacy of PI3Kα inhibitors combined with PD‐1 antibodies is promising in cervical cancer and warrants additional clinical and mechanistic investigations.

Beyond Canonical Immune Checkpoints: Overexpression of TNFRSF Members 4‐1BB and OX‐40 Marks T Cells Exhibiting Phenotypic Features of Exhaustion in Cervical Carcinoma

ABSTRACTT cells are pivotal in combating cancer; however, they can become exhausted during tumour progression, losing their cytotoxic capacity and upregulating inhibitory receptors including PD‐1 and TIGIT. While checkpoint blockade has emerged as a potent treatment option for numerous cancers, patient selection, long‐term efficacy, and adverse effects still remain an issue. For these reasons, it is important to investigate other pathways that might lead to selective reactivation of the immune system. Co‐stimulatory TNFRSF receptors, including 4‐1BB and OX‐40, have emerged as promising targets for reactivating exhausted T cells. However, their expression on exhausted peripheral and tumour‐infiltrating lymphocytes (TILs) is not well characterised, particularly in cervical cancer (CC), which remains the leading cause of gynaecological cancer mortality in low‐ and middle‐income countries. To investigate the expression of these receptors, PBMCs were collected from CC patients and healthy donors, along with TILs from tumour biopsies, and analysed using multiparametric flow cytometry. Our findings revealed an increased population of phenotypically exhausted (PD‐1+TIGIT+) CD4+ and CD8+ T cells in TILs, and, to a lesser extent, in peripheral blood and from CC patients. These exhausted T cell subsets exhibited selective overexpression of 4‐1BB and OX‐40 compared to phenotypically non‐exhausted cells (PD‐1−TIGIT−). In TILs, 4‐1BB was overexpressed 12.7‐fold in CD8 cells with the exhausted phenotype, OX‐40 was overexpressed 3.3‐fold; in CD4 cells with the exhausted phenotype, the overexpression was 7.8× and 3.8× for 4‐1BB and OX‐40, respectively. CD8 and CD4 T cells that were PD‐1 + TIGIT+ 4‐1BB+ were 7.3× and 16× more likely to be found in the tumour versus peripheral blood. Additionally, subpopulations of PD‐1high T cells were significantly elevated in the tumour‐infiltrating T cells and TIGIT expression was positively associated with PD‐1 levels in peripheral patient CD8+ and CD4+ T cells, potentially indicating an advanced state of exhaustion. These findings suggest that TNFRSF members, especially 4‐1BB, may serve as potential immunotherapeutic targets for reinvigorating exhausted T cells in CC.