Was going to mention the same thing about researchers thinking it's a good idea to combine anti-PD-1/PD-L1 with CCR5 blockade as complementary / non-overlapping pathways from that paper.
https://onlinelibrary.wiley.com/doi/abs/10.1111/exd.14065
Other authors recognize some overlap:
https://www.sciencedirect.com/science/article...0X19300612
Here is a similar recent article showing that inflammatory macrophages near tumor cells secrete CCL5, which then stabilizes PD-L1 on tumor cells. Perhaps LL could keep the macrophages away or re-polarize them so they won't secrete CCL5?
https://www.nature.com/articles/s41418-019-0460-0
So, it looks like CCL5/CCR5 and PD-L1 do interact, and I think the pathways could be complementary. It's also possible that CCR5 blockade alone could do the trick, but we have to run the trials to find out.
and as ohm noted, the recent paper about the PD-L1 pathway and CCR5 in a BAP-1 mutant mouse model of CRC:
https://jitc.bmj.com/content/8/1/e000228
So even the authors whose work ohm qouted suggest the pathways could be complementary.
Lots of recent work has shown that immune checkpoint modulation is dependent on the tumor microenvironment, and even somehow the gut immune environment.
Hopefully blockade of CCL5/CCR5 can create a better tumor immune microenvironment where the proper immune system killer T-cells can get in there to eliminate the tumor without being shut down (by T-Regs, CCL5 secreting macrophages, PD-L1, etc...).
Combo trials make sense, and are already ongoing with maraviroc and the BMS CCR2/CCR5 drug.
Another review talking about the trials:
https://www.mdpi.com/2072-6694/12/7/1765/htm
Some results of one such trial from ASCO last year:
https://ascopubs.org/doi/abs/10.1200/JCO.2020...suppl.3010
https://onlinelibrary.wiley.com/doi/abs/10.1111/exd.14065
Quote:
Blockade of CCR5 can be combined with anti‐PD‐1/PD‐L1 with or without anti‐CTLA‐4 drugs since it targets a non‐overlapping pathway. The addition of CCR5 blockade could help decrease the dose of PD1 inhibitors and therefore improve the side effect profile, which is a major obstacle to the use of immunotherapy. While anti‐PD‐1/PD‐L1 enables T‐cell anti‐tumor activity, blockade of CCR5 can prevent MDSCs and T‐regs immune modulation and prevent neutrophilic‐mediated inflammation in the tumor microenvironment.
Other authors recognize some overlap:
https://www.sciencedirect.com/science/article...0X19300612
Quote:Moreover, several lines of evidence suggest that CCR5 and its ligands appear to participate in the canonical immune check point response. The Programmed Cell Death Protein 1 (CD279 and PD-1) and its ligand PD-1 Ligand (PD-L1) signaling pathway are critical players in immune checkpoints. PD-1 signaling plays an important role in tumor evasion from the innate immune system. In addition, tumor-infiltrating lymphocytes (TILs) serve as a biomarker for predicting responses to PD-L1 blockade therapy. Recent evidence supports that tumors responsive to immunotherapy tend to infiltrate with T cells in response to CTLA-4 and PD-1 antagonism; this process is referred to as a “T cell-inflamed” tumor microenvironment (Gajewski, 2015; Ji et al., 2012; Tumeh et al., 2014). CCL5 upregulation was demonstrated in PD-L1-positive melanoma tumors along with IFNγ and several IFNγ-related genes (Ayers et al., 2017; Taube et al., 2015). Tumor burden and a T cell-inflammatory gene expression were independently predictive of the response to the PD-1 antibody pembrolizumab (Cristescu et al., 2018).
It is also important to analyze the role of MDSC. CCR5high MDSC have higher immunosuppressive activity than CCR5low MDSC (Chang, Lin, Kang, et al., 2012), and when disrupted, MDSC trafficking enhances anti-PD1 therapy (Highfill et al., 2014). As described above, CCL5 promotes not only the influx of CD8+ T-cells (Harlin et al., 2009), but also the expression of PD-L1 when associated with increased TILs. Relatedly, the Keynote-028 study demonstrated that the tumors with high PD-L1 and T cell inflammatory gene expression, were associated with a positive outcome from monoclonal antibody therapy (pembrolizumab) (Seto et al., 2019). Collectively, these studies suggest that overlap exists between the CCR5 non-canonical and canonical immune checkpoint pathways.
Here is a similar recent article showing that inflammatory macrophages near tumor cells secrete CCL5, which then stabilizes PD-L1 on tumor cells. Perhaps LL could keep the macrophages away or re-polarize them so they won't secrete CCL5?
https://www.nature.com/articles/s41418-019-0460-0
Quote:C-C motif chemokine ligand 5 (CCL5), which is secreted by macrophages, inhibited T-cell-mediated killing of HT29 cells and promoted immune escape by stabilizing PD-L1 in vitro and in vivo. Mechanistically, CCL5 resulted in formation of nuclear factor kappa-B p65/STAT3 complexes, which bound to the COP9 signalosome 5 (CSN5) promoter, leading to its upregulation. Moreover, CSN5 modulated the deubiquitination and stability of PD-L1. High expression of CSN5 in CRC was associated with significantly shorter survival.
..
We propose that CCL5 secreted by macrophages induces the upregulation of PD-L1 in cancer cells, which in turn promotes the infiltration of macrophages, forming a positive feedback loop that facilitates immune escape of cancer cells and subsequently the growth of CRC.
So, it looks like CCL5/CCR5 and PD-L1 do interact, and I think the pathways could be complementary. It's also possible that CCR5 blockade alone could do the trick, but we have to run the trials to find out.
and as ohm noted, the recent paper about the PD-L1 pathway and CCR5 in a BAP-1 mutant mouse model of CRC:
https://jitc.bmj.com/content/8/1/e000228
Quote:Taken together, these results indicated that CCR5 blockade could enhance the ability of the host immune system to eliminate tumor cells.
..
Besides recruiting CCR5+ Tregs, we also found that BAP1-mutant tumor cells generated CCL2, CCL3 and CCL5, which bound to CCR5 on the cell surface and induced PD-L1 expression. This process could be attenuated by CCR5 inhibitors.
..
These results suggested that combining use of PD-1 inhibitor and maraviroc in BAP1-mutant patients with ccRCC is a direction worth exploring in the future.
The present work has some limitations. The specific mechanism that the CCL5-CCR5 axis induces tumor cells to express PD-L1 at high levels needs to be further elucidated. Additionally, the mechanism by which BAP1 mutation leads to increased expression of CCR5 and its ligands remains to be investigated.
So even the authors whose work ohm qouted suggest the pathways could be complementary.
Lots of recent work has shown that immune checkpoint modulation is dependent on the tumor microenvironment, and even somehow the gut immune environment.
Hopefully blockade of CCL5/CCR5 can create a better tumor immune microenvironment where the proper immune system killer T-cells can get in there to eliminate the tumor without being shut down (by T-Regs, CCL5 secreting macrophages, PD-L1, etc...).
Combo trials make sense, and are already ongoing with maraviroc and the BMS CCR2/CCR5 drug.
Another review talking about the trials:
https://www.mdpi.com/2072-6694/12/7/1765/htm
Quote:Clinical trials with the CCR5 antagonists maraviroc, leronlimab, vicriviroc and BMS-813160 [17] in triple-negative breast cancer, colorectal cancer, Kaposi’s sarcoma, and advanced pancreatic ductal carcinoma are completed, ongoing or recruiting (Table 3). CCR5 antagonists are being tested in combination with the checkpoint inhibitors pembrolizumab and nivolumab, humanized monoclonal anti-PD-1 antibodies that block PD-1 on T cells, preventing their inactivation by PD-L1 expressed by cancer cells, TAMs, and CAFs.
Some results of one such trial from ASCO last year:
https://ascopubs.org/doi/abs/10.1200/JCO.2020...suppl.3010
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