182P CD27-IgD- B cells might portray an exhausted B cell phenotype resulting in lack of response to checkpoint inhibitor treatment in NSCLC

Checkpoint inhibitor (CI) therapy has revolutionized the therapy landscape of NSCLC. However, why some patients do not respond to CI therapy remains unknown. The correlation between intra-tumoral B cell follicles and response to CI therapy has been established. B cell follicles within the lymph node become more dispersed with age and CD27-IgD- B cells (DNBc) are described to be age-associated. Moreover, DNBc are abundant in chronic infection, elderly, long COVID and auto-immunity and are described to be anergic and exhausted and often lack expression of CD21. DNBc are expanded in NSCLC tumors compared to healthy lung tissue and inversely correlate to switched memory B cells in the tumor. In this study we explored if there is a correlation between this B cell subtype in peripheral blood of NSCLC patients and response to CI therapy. Patients treated with CIs within the Erasmus Medical Center were included in a prospective observational immunomonitoring study. Nineteen NSCLC patients treated with either Pembrolizumab (Pem) or Nivolumab and 5 healthy controls (HC) were selected. Pem was given in 6/11 responding patients (R) and 5/8 non-responding patients (NR). Peripheral blood mononuclear cells (PBMC) were collected before start of treatment and characterized by multicolor flow cytometry. HC and R showed a similar pattern in most B cell subsets. NR had significantly lower proportion of B cells within the PBMC fraction than Rand HC (R: 7.14%, NR: 2.91%, HC: 10.60%). In addition, NR had a significantly higher frequency of DNBc than R and HC (R: 9.43%, NR: 23.78%, HC: 7.19%) and there was no correlation between age and DNBc. The frequency of DNBc correlated positively with lack of CD21 expression (r2: 0.83) and expression of Ki67 (r2: 0.54) both in NR, Rand HC. The frequency of Ki67+CD21-DNBc within the B cell fraction was higher in NR than in R and HC (NR: 18.34%, R: 3.51%, HC: 0.67%). We are the first to describe that frequencies of DNBc are higher in NR compared to R and HC. Specifically, Ki67+CD21-DNBc are increased in NR and might reflect an anergic, exhausted B cell phenotype. The absence of a correlation between age and DNBc could suggest that the increase in DNBc is induced by the tumor.