Reversal of the immunosuppressive tumor microenvironment via platinum-based neoadjuvant chemotherapy in cervical cancer

Abstract

Background

Immunotherapy favors patients with tumors; however, only 3–26.3% of patients with cervical cancer benefit from single-agent immune checkpoint inhibitors. Combined immunotherapy and chemotherapy has been explored against tumor; however, the combination remains controversial. This study aimed to investigate the tumor immune microenvironment (TIME) and the effects of platinum-based neoadjuvant chemotherapy (NACT) in cervical cancer to identify the clinical value of combining chemotherapy with immunotherapy.

Methods

Multiplex immunohistochemistry (IHC) with 11 markers (cluster of differentiation [CD]3, CD8, CD4, CD11c, CD68, forkhead box P3 [Foxp3], programmed cell death 1 [PD-1], programmed cell death 1 ligand 1 [PD-L1], indoleamine 2,3-dioxygenase [IDO], cyclin-dependent kinase inhibitor 2A [p16], and cytokeratin [CK]) was performed to evaluate TIME from 108 matched pre- and post-NACT cervical cancer samples. The mechanism of antitumor immunity triggered by NACT was explored using RNA sequencing (RNA-seq) from four paired samples and subsequently verified in 41 samples using IHC.

Results

The infiltration rate of the CD8⁺ T cells in treatment-naive cervical cancer was 0.73%, and those of Foxp3⁺ regulatory T cells (Tregs) and IDO⁺ cells were 0.87% and 17.15%, respectively. Moreover, immunoreactive T cells, dendritic cells, and macrophages were more in the stromal than the intratumor region. NACT increased dendritic, CD3⁺ T, CD8⁺ T, and CD4⁺ T cells and decreased Tregs. The aforementioned alterations occurred predominantly in the stromal region and were primarily in responders. Non-responders primarily showed decreased Tregs and no increase in CD8⁺ T or dendritic cell infiltration. Furthermore, dendritic cells interacted more closely with CD3⁺ T cells after NACT, an effect primarily observed in responders. RNA-seq data revealed activation of the antigen receptor-mediated signaling pathway and upregulation of major histocompatibility complex (MHC) I and MHC II after chemotherapy, validated using IHC.

Conclusions

NACT can reduce Tregs, and when tumor cells are effectively killed, antigen presentation is enhanced, subsequently activating antitumor immunity finitely. Our study provides the molecular characteristics and theoretical basis for the simultaneous or sequential combination of platinum-based NACT and immunotherapy for cervical cancer.