On the one hand, some failures to response to neoantigen vaccines are primarily attributed to suppressive tumor microenvironment. Emerging immune modulators including anti-PD-1/PD-L1 antibody, anti-CTLA-4 antibody, and anti-T cell immunoglobulin and mucin domain-containing protein-3 (Tim-3) antibody could resolve the problem [
71,
72]. Sahin et al. conducted a study to explore the treatment effect of RNA platform-based neoantigen cancer vaccine [
73]. One out of three melanoma patients receiving vaccine experienced relapse and distant metastasis. However, by subsequent pembrolizumab treatment, the patient showed a complete response [
73]. Compared with the reported complete response rate (below 10%), this treatment effect is satisfactory [
73]. Further investigation revealed that neoantigen specific T cell was PD-1
+, and the expression abundance of PD-L1 in tumor tissue was upregulated, suggesting the suppressive immune microenvironment induced by neoantigen cancer vaccine [
73]. Presumably due to blockaded inhibitory immune regulation, the combination therapy showed more robust tumor control effect [
73]. Simultaneously, Ott et al. investigated the efficacy of neoantigen cancer vaccine targeting up to 20 predicted neo-epitopes [
74]. It was showed that 2 out of 6 melanoma patients experienced tumor relapse [
74]. Similarly to the phenomenon mentioned above, both 2 recurrent melanoma patients had a complete tumor rejection after pembrolizumab treatment, which further verified the feasibility of combination therapy [
74].
On the other hand, frequently-occurring adaptive resistance during immune checkpoint inhibitor is related with variation of neoantigen repertoire [
67]. Due to heterogeneity of tumor, part of mutations are shared by all tumor cells while the others are exclusively expressed by subpopulations [
75]. Under survival selective pressure, subpopulations sensitive to immune checkpoint inhibitor are eliminated. In the meanwhile, subpopulations resistant to immune checkpoint inhibitor have an advantage in proliferation [
76]. As a result, loss of immunologic epitopes results in alternative subpopulation constitution and resistance to treatment, called immunoediting [
77,
78]. However, the resistance could be overcome by neoantigen cancer vaccine, because immune-stimulating component of vaccine could be manipulated depending on dynamic variation of neoantigen spectrum during tumor evolution [
67]. Carreno et al. conducted a study to investigate the influence of neoantigen cancer vaccine on neoantigen-specific T cell receptor repertoire [
79]. The study recruited 3 melanoma patients which had been treated with ipilimumab [
79]. Each patient received DC platform-based neoantigen cancer vaccine which containing 7 identified neoantigens [
79]. Before and after vaccination, researchers collected peripheral blood sample and estimated the immune response to supposed neoantigens [
79]. Immune monitoring showed that T cell response targeting these neoantigens was enhanced. Moreover, compared with pre-vaccination, vaccination induced T cell response to 2 additional neoantigens per patient [
79]. Subsequently, composition and abundance of neoantigen-specific T cell was analyzed. In the purified CD8
+ T cell isolated from peripheral blood, researchers found that after vaccination, the frequency of existing neoantigen-specific TCRβ clonotypes were increased accompanied with additional clonotypes for all each neoantigen [
79]. The results showed that both TCRβ clonotypes targeting predominant and sub-predominant neoantigens were elevated after vaccination, suggesting the broadened spectrum of T cell response [
79]. Two patients recruited in the study were resistant to ipilimumab and had recurrent tumor lesions. By intervention of neoantigen cancer vaccine, effective anti-tumor immune response was rebuilt [
79].