Blockade of only TGF-β 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy

Abstract

Checkpoint inhibition has established immunotherapy as a major modality of cancer treatment. However, the success of cancer immunotherapy is still limited as immune regulation of tumor immunity is very complicated and mechanisms involved may also differ among cancer types. Beside checkpoints, other good candidates for immunotherapy are immunosuppressive cytokines. TGF-β is a very potent immunosuppressive cytokine involved in suppression of tumor immunity and also necessary for the function of some regulatory cells. TGF-β has three isoforms, TGF-β 1, 2 and 3. It has been demonstrated in multiple mouse tumor models that inhibition of all three isoforms of TGF-β facilitates natural tumor immunosurveillance and tumor vaccine efficacy. However, individual isoforms of TGF-β are not well studied yet. Here, by using monoclonal antibodies (mAbs) specific for TGF-β isoforms, we asked whether it is necessary to inhibit TGF-β3 to enhance tumor immunity. We found that blockade of TGF-β1 and 2 and of all isoforms provided similar effects on tumor natural immunosurveillance and therapeutic vaccine-induced tumor immunity. The protection was CD8 T cell-dependent. Blockade of TGF-β increased vaccine-induced Th1-type response measured by IFNγ production or T-bet expression in both tumor draining lymph nodes and tumors, although it did not increase tumor antigen-specific CD8 T cell numbers. Therefore, protection correlated with qualitative rather than quantitative changes in T cells. Furthermore, when combined with PD-1 blockade, blockade of TGF-β1 and 2 further increased vaccine efficacy. In conclusion, blocking TGF-β1 and 2 is sufficient to enhance tumor immunity, and it can be further enhanced with PD-1 blockade.

Intratumorally delivered formulation, INT230-6, containing potent anticancer agents induces protective T cell immunity and memory

“…23,24 Our laboratory has published multiple studies delivering effective cancer vaccines subcutaneously next to the tumor site rather than intramuscularly. [25][26][27] Local administration has the advantage of delivering a higher dose to the tumor site with the potential for less systemic toxicity. Local cancer vaccine treatment may also help to overcome a lack of immune response in cold tumors.…”

Checkpoint blockade in solid tumors and B-cell malignancies, with special consideration of the role of CD200

“…Blockade of TGF-β1 and TGF-β2, in association with a therapeutic vaccine-inducing CD8 + T-cell-mediated tumor immunity, led to augmented protection and increased vaccine-induced Th1-type responses as measured by IFNγ production. 43 Most importantly, when combined with PD-1 blockade, additional blockade of TGF-β1 and TGF-β2 led to even further increased vaccine efficacy. 43 …”

“… 43 Most importantly, when combined with PD-1 blockade, additional blockade of TGF-β1 and TGF-β2 led to even further increased vaccine efficacy. 43 …”

Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural Insights from a Computational Model

“…For instance, the N1→N2 transition of TANs with protumour properties was typically observed in a TGF-β-rich TME and the presence of IFN-β or TGF-β inhibitor can mediate the reverse transition (N2→N1) with anti-tumoral properties [3]. Therefore, TGF-β pathway inhibitors are under clinical trials since they were shown to promote the development of N1 TANs [68,69]. (iii) N1 and N2 phenotypes proliferate at a rate, λ 1 and λ 2 (G), respectively.…”