Neoantigen-specific CD4⁺T-cell response is critical for the therapeutic efficacy of cryo-thermal therapy

Abstract

BackgroundTraditional tumor thermal ablations, such as radiofrequency ablation (RFA) and cryoablation, can result in good local control of tumor, but traditional tumor thermal ablations are limited by poor long-term survival due to the failure of control of distal metastasis. Our previous studies developed a novel cryo-thermal therapy to treat the B16F10 melanoma mouse model. Long-term survival and T-cell-mediated durable antitumor immunity were achieved after cryo-thermal therapy, but whether tumor antigen-specific T-cells were augmented by cryo-thermal therapy was not determined.MethodsThe long-term antitumor therapeutic efficacy of cryo-thermal therapy was performed in B16F10 murine melanoma models. Splenocytes derived from mice treated with RFA or cryo-thermal therapy were coincubated with tumor antigen peptides to detect the frequency of antigen specific CD4+ and CD8+ T-cells by flow cytometry. Splenocytes were then stimulated and expanded by αCD3 or peptides and adoptive T-cell therapy experiments were performed to identify the antitumor efficacy of T-cells induced by RFA and cryo-thermal therapy. Naïve mice and tumor-bearing mice were used as control groups.ResultsLocal cryo-thermal therapy generated a stronger systematic antitumor immune response than RFA and a long-lasting antitumor immunity that protected against tumor rechallenge. In vitro studies showed that the antigen-specific CD8+ T-cell response was induced by both cryo-thermal therapy and RFA, but the strong neoantigen-specific CD4+ T-cell response was only induced by cryo-thermal therapy. Cryo-thermal therapy-induced strong antitumor immune response was mainly mediated by CD4+ T-cells, particularly neoantigen-specific CD4+ T-cells.ConclusionCryo-thermal therapy induced a stronger and broader antigen-specific memory T-cells. Specifically, cryo-thermal therapy, but not RFA, led to a strong neoantigen-specific CD4+ T-cell response that mediated the resistance to tumor challenge.

Differentiation and Regulation of TH Cells: A Balancing Act for Cancer Immunotherapy

“…In three murine models of melanoma (B16F10), breast (4T1) and colon (CT26) cancer, the majority of the mutated neo-epitopes were recognized by CD4 + T cells, and vaccination with such mutations elicit robust tumor rejection ( 176 ). A recent study published with 4T1 and B16F10 murine models tested therapeutic efficacy of a novel cryo-thermal therapy with respect to conventional radiofrequency ablation and showed strong neoantigen-specific CD4 + T-cell response induced by cryo-thermal therapy, resulting in anti-tumor immune response and long-lasting protection against tumor re-challenge ( 177 ). Combination of local radiotherapy with an RNA-LPX vaccine that encodes CD4 + T cell-recognized neoantigens resulted in a poly-antigenic, potent CD8 + T cell response and memory that rejected CT26 tumor re-challenge, had higher number of polyfunctional IFN-γ + CD4 + T H 1 cells specific for the immunodominant CD4 neoantigen ME1, elevated numbers of activated gp70-specific CD8 + T cells, and lower PD-1/LAG-3 expression.…”

Identification of 15 lncRNAs Signature for Predicting Survival Benefit of Advanced Melanoma Patients Treated with Anti-PD-1 Monotherapy

“…T cells are prominent TILs in melanoma [ 55 ]. CD4 + T cells are associated with anti-tumor responses in melanoma [ 56 , 57 , 58 ]; CD8 + T cells also play a role herein [ 59 ]. Further, different CD8 + T cell subpopulations have predictive value in melanoma [ 60 ].…”

Iron Released after Cryo-Thermal Therapy Induced M1 Macrophage Polarization, Promoting the Differentiation of CD4+ T Cells into CTLs

“…Our previous studies demonstrate that cryo-thermal therapy can not only effectively ablate tumors locally but also induce systematic antitumor immunity [8][9][10]15,17,44,46,47]. After cryo-thermal therapy, tumors in situ release tumor antigens and danger signals, which facilitate a durable antitumor adaptive immune response [15,17,47]. However, the existing research had not yet addressed whether other components released from tumors in situ after cryo-thermal therapy trigger host immunity.…”