Tumors with high mutational burden (TMB) tend to be responsive to immune checkpoint blockade (ICB) because there are neoantigens available for targeting by reinvigorated T cells, whereas those with low TMB demonstrate limited clinical responses. To determine whether antigen-specific T cell responses can be elicited after treatment with ICB in cancers that have a low TMB, we conducted a clinical trial with ipilimumab in 30 patients with metastatic castration-resistant prostate cancer. We identified two distinct cohorts by survival and progression times: “favorable” (n = 9) and “unfavorable” (n = 10). Patients in the favorable cohort had high intratumoral CD8 T cell density and IFN-γ response gene signature and/or antigen-specific T cell responses. Two patients with a relatively low TMB had T cell responses against unique neoantigens. Moreover, six of nine patients in the favorable group are still alive at the time of analysis, with survival ranging from 33 to 54 months after treatment. All 10 patients in the unfavorable cohort have succumbed to their disease and had survival ranging from 0.6 to 10.3 months. Collectively, our data indicate that immunological correlates associated with effector T cell responses are observed in patients with metastatic prostate cancer who benefit from ICB.

具有高突变负担（TMB）的肿瘤倾向于对免疫检查点阻断（ICB）作出反应，因为有新抗原可用于重新活化的T细胞靶向，而具有低TMB的肿瘤表现出有限的临床反应。为了确定在TMB低的癌症中用ICB治疗后是否能引起抗原特异性T细胞应答，我们对30名转移性去势抵抗性前列腺癌患者进行了ipilimumab的临床试验。我们通过生存和进展时间确定了两个截然不同的队列：“有利”（n = 9）和“不利”（n= 10）。有利队列中的患者具有高的肿瘤内CD8 T细胞密度和IFN-γ应答基因标记和/或抗原特异性T细胞应答。两名TMB相对较低的患者对独特的新抗原具有T细胞反应。此外，在分析时，有利组中的9名患者中有6名仍然活着，存活时间为治疗后33到54个月。不利队列中的所有10名患者都死于疾病，生存时间为0.6到10.3个月。总体而言，我们的数据表明，在受益于ICB的转移性前列腺癌患者中观察到了与效应T细胞反应相关的免疫学相关性。