Antigen-specific primed cytotoxic T cells eliminate tumour cells in vivo and prevent tumour development, regardless of the presence of anti-apoptotic mutations conferring drug resistance

Abstract

Cytotoxic CD8 T (Tc) cells are the main executors of transformed and cancer cells during cancer immunotherapy. The latest clinical results evidence a high efficacy of novel immunotherapy agents that modulate Tc cell activity against bad prognosis cancers. However, it has not been determined yet whether the efficacy of these treatments can be affected by selection of tumoural cells with mutations in the cell death machinery, known to promote drug resistance and cancer recurrence. Here, using a model of prophylactic tumour vaccination based on the LCMV-gp33 antigen and the mouse EL4 T lymphoma, we analysed the molecular mechanism employed by Tc cells to eliminate cancer cells in vivo and the impact of mutations in the apoptotic machinery on tumour development. First of all, we found that Tc cells, and perf and gzmB are required to efficiently eliminate EL4.gp33 cells after LCMV immunisation during short-term assays (1-4 h), and to prevent tumour development in the long term. Furthermore, we show that antigen-pulsed chemoresistant EL4 cells overexpressing Bcl-X or a dominant negative form of caspase-3 are specifically eliminated from the peritoneum of infected animals, as fast as parental EL4 cells. Notably, antigen-specific Tc cells control the tumour growth of the mutated cells, as efficiently as in the case of parental cells. Altogether, expression of the anti-apoptotic mutations does not confer any advantage for tumour cells neither in the short-term survival nor in long-term tumour formation. Although the mechanism involved in the elimination of the apoptosis-resistant tumour cells is not completely elucidated, neither necroptosis nor pyroptosis seem to be involved. Our results provide the first experimental proof that chemoresistant cancer cells with mutations in the main cell death pathways are efficiently eliminated by Ag-specific Tc cells in vivo during immunotherapy and, thus, provide the molecular basis to treat chemoresistant cancer cells with CD8 Tc-based immunotherapy.

Pyroptosis: a new paradigm of cell death for fighting against cancer

“…The CCCR-modified NK92 cells exhibit augmented activity against human lung cancer H1299 cells in vitro through induction of extensive pyroptosis [ 132 ]. However, another study argued that tumor suppression by antigen-specific primed cytotoxic T cells is independent of necroptosis or pyroptosis [ 133 ]. Thus, pyroptosis is an immune-stimulatory form of cell death and can synergize with immune checkpoint agents to improve the efficacy of immune therapy.…”

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

“…In our current understanding, induction of apoptosis is the main mechanism of CTLs and NK-cells to kill tumor-cells with some reported exceptions [53]. CTLs and NK-cells are known to utilize both the extrinsic and intrinsic pathways to induce apoptosis.…”

Perforin and Granzyme B Expressed by Murine Myeloid-Derived Suppressor Cells: A Study on Their Role in Outgrowth of Cancer Cells

“…We consequently considered using KO mice. However, tumors do not develop well in these mice [24,33]. Moreover, the lack of perforin and GzmB in this model is not confined to MDSCs, thus, any conclusions drawn could be confounded by other perforin and GzmB expressing immune cell populations, such as Tregs, CTLs, and NK cells [5,24].…”