PD-L1 immune checkpoint inhibition in combination with radiation across different bladder cancer molecular subtypes and influences on immune memory

Bladder cancer is the 5th most prevalent cancer in Canada. 30% of the cases are muscle-invasive (MIBC). MIBC is a highly lethal disease; the patient survival rate has not improved over the last decades, and treatments option is limited. The standard gold treatment is radical cystectomy; however, more than 40% of the patients are unfit to undergo surgery. Hence, new strategies to improve treatments for MIBC are imperative. Radiotherapy (RT) is an alternative treatment and allows bladder preservation. Although it maintains the quality of life, half of the patients will develop metastasis. RT can enhance tumor antigen presentation, but it can also induce a higher expression of programmed-cell-death1(PD-1) on T cells and programmed-cell-death-ligand1(PD-L1) on cancer cells. This interaction causes T cell exhaustion and impairs the immune response against cancer. The effect can be prevented by the addition of anti-PD-L1 molecules, which will result in an increase of infiltrating T cells. Thus, combining immunotherapy with RT may boost the systemic immune response leading to improving oncological outcomes of bladder preserving strategies. Our lab has previously shown an abscopal response when treated with the combined treatment, which proved the efficacy of the combination. However, immunological memory is required for durable response, which could prevent metastasis and recurrence. We hypothesize that the combination of radiotherapy and immunotherapy will generate the development of immunological memory, which is needed for long-lasting responses. To analyze the different responses to the combinational treatment, we used different murine bladder cancer cell lines and characterized the tumor microenvironment and the immune memory profile. MB49 represents the basal molecular subtype and a hot tumor model. UPPL represents the luminal molecular subtype and a cold tumor model. The baseline characterization of the immune response was compared between the two molecular subtypes of bladder cancer. MB49 had a higher T cell infiltration compared to UPPL. UPPL had a higher infiltration of neutrophils. The induction of memory was assessed by comparing the memory populations across treatment groups: control, RT, anti-PD-L1 and RT + anti-PD-L1. Following treatment, the tumors were excised via surgery to create a tumor-free, tumor antigen encountered mice model. Mice deemed tumor-free after 5 weeks without tumor growth in the right flank were re-challenge with a second cancer cell injection in the opposite flank. This tumor re-challenge growth kinetics determined the memory response. The combined treatment was expected to produce a larger and effective pool of memory T cells compared to other treatment groups by generating long-term immune memory, which would correlate with either tumor rejection or growth delay in the re-challenge. A distinct immune profile was expected in response to combination therapy across the molecular subtypes. Findings from this study will have a very important clinical relevance as it provides evidence for a more sustained clinical response using combination therapy across different molecular subtypes. Importantly, the potential of eliminating micrometastatic disease using augmented systemic effects of the combined approach is highly promising

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