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on ADCC activity has not been collected, and the possibility that there are individual differences in the
number or function of host immune cells that exert ADCC activity. The search for further mechanisms and
factors involved in ADCC is desirable.

Immune-checkpoint inhibitors
In recent years, ICIs that activate the exhausted immune cells by inhibiting immune checkpoint molecules
typified by CTLA4 and PD-1/PD-L1 pathways with antibody drugs have been key drugs for the treatment
of malignant melanoma and non-small cell lung cancer. To date, 1 anti-CTLA4 antibody (ipilimumab),
2 anti-PD-1 antibodies (nivolumab and pembrolizumab), and 3 anti-PD-L1 antibodies (atezolizumab,
durvalumab, and avelumab) have been marketed. Anti-PD-1 antibodies have IgG1 isoforms, and the
other ICIs have IgG4 isoforms. All drugs have anti-tumor effects, mainly due to neutralization or signal
inhibition, with dramatic therapeutic effects in many cancer types such as malignant melanoma, NSCLC,
[38]
and merkel cell carcinoma . However, ICIs have unclear drug efficacy biomarkers, and they cause
immune-related adverse events (irAEs) that are different from the adverse events of conventional anticancer
drugs. IrAEs occur due to the activation of host immunity by ICIs, causing immune response disorders
and hormonal abnormalities in organs such as the thyroid, lungs, and pancreas. Although myelotoxicity
and gastrointestinal toxicity are less likely than with cytotoxic chemotherapy, irAEs can sometimes be life
threatening. Moreover, various biomarker searches for PD-1 inhibitors, which are frequently used in clinical
practice, have been investigated. Tumor PD-L1 expression, tumor mutation burden (TMB), T cell receptor
[39]
(TCR) repertoire, human leukocyte antigen (HLA), microbiome, etc. are attracting attention . ICIs
activate host immunity by blocking the co-stimulatory/inhibitory pathway with antibody drugs, but the
major signaling pathway of antigen-presenting cells and T cells is the binding of major histocompatibility
complex (MHC) and TCR. Antigen-presenting cells present peptides produced from tumors as antigens,
which are recognized by TCRs. From the above, peptides presented as antigens are factors on the tumor
side, and MHC and TCR are factors on the host side.

Tumor antigen peptides that are factors on the tumor side include cancer testis antigens such as the
melanoma-associated antigens (MAGEAs) and New York esophageal squamous cell carcinoma 1 that
are expressed in tumors regardless of gene mutations, and tumor antigen peptides generated by tumor
gene mutations. The number of tumor non-synonymous mutations is called the TMB, and it is attracting
attention as an index of tumor immunogenicity, especially in melanoma and NSCLC that typically
have high mutation burdens due to the mutagenic effects of ultraviolet light and cigarette smoking,
[40]
[41]
respectively . In 2014, Snyder et al. performed 64 whole-exome sequencing of melanoma patients
treated with CTLA-4 antibody and showed significantly higher TMB in patients with stable or responsive
[41]
disease for more than 6 months, and TMB more than 100 was associated with better overall survival .
This result was confirmed by examination of CTLA-4 antibody against other malignant melanoma cohorts,
and it was shown that the higher the TMB of non-small cell lung cancer, the better the response rate and
PFS of PD-1 antibody [42,43] . Since then, many cancer types have been shown to have a linear response rate
[44]
with TMB, and it has become clear that TMB can help predict certain therapeutic effects . However,
some cancer types do not follow this linear response. For example, merkel cell carcinoma and renal
cell carcinoma are more sensitive than expected to TMB, whereas misamatch-repair (MMR)-proficient
colorectal cancer is less sensitive than expected. That is, although TMB has some degree of correlation
with the therapeutic effect, other factors are also assumed to be related to the therapeutic effect of ICIs.
In addition, technical issues still remain, such as the fact that TMB does not have a confirmed calculation
method and cut-off criteria, and whether analysis samples are performed with tumor samples or cell-free
DNA.

Like TMB, DNA MMR defects (MMRds) are considered biomarkers of ICIs by causing somatic mutations.
Le et al. [45,46] showed that pembrolizumab had a response rate of 53% in 86 cases with 12 cancer types of