Injured Tumor Cells Promote Anti-tumor Immunity

With the development of immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4, immunotherapy has emerged as a highly promising approach to revolutionize cancer treatments. Certain tumor types exhibit remarkable clinical responses to immunotherapy, in particular melanoma, non-small cell lung cancer and colon cancer. However, for most patients with common cancer types, including breast and ovarian cancers, are less likely to respond to immunotherapy and less than 13% of cancer patients respond to immune checkpoint inhibitors alone.

Based on their long-standing interest in identifying mechanisms that would enhance cancer response to the combination of immune checkpoint blockade and chemotherapy, Sriram et al. took advantage of the “cross-talk” between the DNA damage response and signalling pathways that mediate tumor cell survival and death to enhance anti-tumor immune responses. 

Sriram et al. treated B16-Ova melanoma cells with clinically used chemotherapeutic agents, etoposide and mitoxantrone and examined them for immunogenicity by measuring their ability to induce dendritic cell-mediated INF-γ responses in CD8⁺ T-cells (Figure 1A). The data in Figure 1B showed that ex vivo chemotherapy-treated tumor cells act as live injured cell adjuvant with the ability to markedly enhance INF-γ production by T-cells. Next, they explored the signalling pathways involved in this process by inhibiting RIPK1, caspase, NF-kB signalling or p38MAPK in B16F10 cells with their respective inhibitors, prior to co-culture with bone-marrow-derived dendritic cells (BMDCs). They found that RIPK1 kinase activity, NF-kB and p38MAPK signalling in live but damaged tumor cells are required for the induction of DC-mediated T-cell IFN-γ responses (Figure 2). 

Figure 1. Experimental system to assess dendritic cell-mediated T-cell IFN- γ responses shows that etoposide- or mitoxantrone-treated B16-Ova, when co-cultured with BMDC, effectively induce INF- γ induction in OT-1 CD8⁺ T-cells. 

Figure2.  Induction of T-cell IFN- γ responses by BDMC co-cultured with etoposide- or mitoxanthrone-treated B16-Ova cells is dependent on RIPK1, NK-kB and p38MAPK signalling in tumor cells

In vivo translation of these findings was achieved by intra-tumoral injection of ex vivo chemotherapy-treated tumor cells as an injured cell adjuvant, in combination with anti-PD1/CTLA4 antibodies (Figure 3A). The subsequent increased intra-tumoral CD103⁺ dendritic cells and circulating tumor antigen-specific CD8⁺ T-cell lead to enhanced anti-tumor immune response and improved survival (Figure 3B). Notably, this therapy induced complete tumor regression in a subset of mice who were then able to reject tumor re-challenge, suggesting the induction of a long-lasting anti-tumor immunological memory (Figure3C,3D). In addition to conducting the tumor re-challenge experiment with live B16-Ova cells, it will be interesting if they can do this with tumor cell that is different from the adjuvant to see whether the antitumor immunity is systemic. 

Figure3. Intra-tumoral administration of ex vivo etoposide-treated B16-Ova cells (injured cell adjuvant) in combination with systemic checkpoint blockade shows enhanced therapeutic benefit and induces long-term immunological memory

Sriram et al.  also suggest a potential method to translate their findings into clinical use. Tumor cells derived from patients could be used to screen the immunogenicity of chemotherapeutic compounds. Tumor cells treated with the optimal compound could then be re-injected into the same tumor in combination with systemic checkpoint blockade. This method has potential for patients whose cancers are accessible for intra-tumoral delivery and in whom conventional treatment options have failed. 

References:

bioRxiv preprint doi: https://doi.org/10.1101/2020.04.26.062216. This version posted April 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.