Table 1.

Summary of current evidence of a humoral immune response in patients treated with checkpoint inhibitor therapy.

Sample type	Time point	CPI used	Target	B cell and antibody responses	Reference
Tumor	Baseline	Ipilimumab	CTLA-4	▪ IL10+ Breg enrichment found in non-responders to anti-CTLA-4 therapy	(22)
				▪ Absence of IGHG gene signature enriched in non-responders to anti-CTLA-4
		Nivolumab	PD-1	▪ IL10+ Breg presence did not correlate with treatment response to anti-PD-1
				▪ IGHG gene signature did not correlate with treatment response to anti-PD-1
Tumor	Baseline	Ipilimumab & Nivolumab combination	CTLA-4 & PD-1	▪ For all treatments increased B cell frequency found in the tumours of responders to both combination therapy and anti-PD-1 monotherapy in both baseline and early on treatment samples	(29)
		Nivolumab	PD-1
	Early on treatment	Ipilimumab & Nivolumab combination	CTLA-4 & PD-1	▪ For all treatments higher density of CD20+ B cells and TLS and a higher TLS:tumour area ratio in early on-treatment samples from responders versus non-responder
		Nivolumab	PD-1	▪ For all treatments increased frequency of switched memory B cells found in responders at baseline and early on treatment
Tumor	Baseline	Ipilimumab	CTLA-4	▪ B cells found to localise within TLS	(27)
				▪ TLS gene signature present in responders’’
				▪ TLS structures associated with CD8+ T cells
Peripheral blood	After 1 year of treatment	Ipilimumab	CTLA-4	▪ High plasmablast numbers seen in patients responding to anti-CTLA-4	(74)
				▪ Sequenced plasmablast antibodies in patients who had not progressed after 1 year had somatic hypermutation, class switching and clonal expansion showing an active humoral response
Tumor	Baseline	Nivolumab	PD-1	▪ Plasmablast-like phenotype (CD19+CD20+CD38+CD138-) found to be most common B cell phenotype in TME	(41)
				▪ Tumour induced plasmablast population (TIBP) defined using melanoma secretome
				▪ Increased expression of TIPB gene signature in baseline samples associated with improved response to Nivolumab
Peripheral blood	Baseline	Nivolumab	PD-1	▪ Melanoma-antigen specific antibodies to: MDA (TRP1/TYRP1, TRP2/TYRP2, gp100, MelanA/MART1) and the Cancer-Testis antigen NY-ESO-1 higher in responders to all treatments	(75)
		Pembrolizumab	PD-1
		Ipilimumab	CTLA-4
		Ipilimumab & Nivolumab combination	CTLA-4 & PD-1	▪ Melanoma-antigen specific IgGs higher in responders at baseline compared with non-responders for all treatments ▪ Melanoma-antigen specific IgGs in patients were mainly IgG1 and IgG2
Peripheral blood	Baseline	Nivolumab	PD-1	▪ For all treatments high titres of IgG, IgG1, IgG2 and IgG3 showed a positive correlation with progression-free survival (PFS)	(76)
		Pembrolizumab	PD-1
		Ipilimumab	CTLA-4
		Ipilimumab & Nivolumab combination	CTLA-4 & PD-1	▪ For all treatments high titre of IgG2 showed a positive correlation with overall survival (OS)
Peripheral blood	Baseline	Ipilimumab & Nivolumab combination therapy	CTLA-4 & PD-1	▪ Overall decline in B cell numbers but increased plasmablast and CD21lo B cell subsets corresponded to development of high grade immune related adverse events (irAE)	(77)
	Early on-treatment
				▪ Changes in other immune cells not significantly associated with frequency or severity of irAE