Neoadjuvant immune checkpoint blockade triggers persistent and systemic T _reg activation which blunts therapeutic efficacy against metastatic spread of breast tumors

Abstract

The clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the neoadjuvant and perioperative setting. However, how neoadjuvant ICB therapy affects the systemic immune landscape and metastatic spread remains to be established. Tumors promote both local and systemic expansion of regulatory T cells (T regs ), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. T regs express inhibitory immune checkpoint molecules and thus may be unintended targets for ICB therapy counteracting its efficacy. Using ICB-refractory models of spontaneous primary and metastatic breast cancer that recapitulate the poor ICB response of breast cancer patients, we observed that combined anti-PD-1 and anti-CTLA-4 therapy inadvertently promotes proliferation and activation of T regs in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, T reg levels were elevated upon ICB. Depletion of T regs during neoadjuvant ICB in tumor-bearing mice not only reshaped the intratumoral immune landscape into a state favorable for ICB response but also induced profound and persistent alterations in systemic immunity, characterized by elevated CD8+ T cells and NK cells and durable T cell activation that was maintained after treatment cessation. While depletion of T regs in combination with neoadjuvant ICB did not inhibit primary tumor growth, it prolonged metastasis-related survival driven predominantly by CD8+ T cells. This study demonstrates that neoadjuvant ICB therapy of breast cancer can be empowered by simultaneous targeting of T regs, extending metastasis-related survival, independent of a primary tumor response.

Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial

“…Whether, next to pretreatment CD8 + PD-1 + levels, the magnitude of this immune activation could be used to distinguish responders from nonresponders will require analysis in a larger cohort. Furthermore, the observed high T reg cell infiltration in nonresponders, together with emerging evidence that T reg cell-targeted approaches may enhance neoadjuvant ICB efficacy, prompt further exploration in future studies 63 . In addition to next-generation anti-CTLA-4, which has been shown to improve T reg cell depletion 64 , 65 , antibodies targeting CCR8, a chemokine receptor selectively expressed on immunosuppressive T reg cells in the TME, are being developed and may provide new avenues 66 , 67 .…”

Chitin-mediated blockade of chitinase-like proteins reduces tumor immunosuppression, inhibits lymphatic metastasis and enhances anti-PD-1 efficacy in complementary TNBC models

“…Production of immunosuppressive T-regs in the TME has been reported to be stimulated by CHI3L1 and can consequently be inhibited by CHI3L1 blockade [ 35 ]. Moreover, our observed significant decrease in T-reg production upon chitin treatment again further emphasizes the beneficial effect on ICB efficacy for human TNBC patients since T-reg amplification upon anti-PD-1 treatment promotes therapeutic resistance [ 56 , 57 ]. Besides providing suppressive modulation of the host immune system, CHI3L1 has a direct impact on tumor cells by activating pathways involved in cellular proliferation, migration, stemness and survival [ 13 , 26 , 35 , 58 – 60 ].…”

Recent research and clinical progress of CTLA-4-based immunotherapy for breast cancer

“…Even after the discontinuation of the treatment, T cells continued to exhibit sustained activation. These findings demonstrate that combination therapy with anti-CTLA-4 antibody, anti-PD-1 antibody, and DT can inhibit Tregs, activate lymphocytes, and promote immune responses in breast cancer model mice ( 67 ).…”