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Somatic mutations in tumor cells give rise to mutant proteins, fragments of which are often presented by MHC and serve as neoantigens. Neoantigens are tumor-specific and not expressed in healthy tissues, making them attractive targets for T-cell-based cancer immunotherapy. On the other hand, since most somatic mutations differ from patient to patient, neoantigen-targeted immunotherapy is personalized medicine and requires their identification in each patient. Computational algorithms and machine learning methods have been developed to prioritize neoantigen candidates. In fact, since the number of clinically relevant neoantigens present in a patient is generally limited, this process is like finding a needle in a haystack. Nevertheless, MHC presentation of neoantigens is not random but follows certain rules, and the efficiency of neoantigen detection may be further improved with technological innovations. In this review, we discuss current approaches to the detection of clinically relevant neoantigens, with a focus on antigen processing and presentation.

Cancer stem‐like cells (CSC)/cancer‐initiating cells (CIC) are defined as minor subpopulations of cancer cells that are endowed with properties of higher tumor‐initiating ability, self‐renewal ability and differentiation ability. Accumulating results of recent studies have revealed that CSC/CIC are resistant to standard cancer therapies, including chemotherapy, radiotherapy and molecular targeting therapy, and eradiation of CSC/CIC is, thus, critical to cure cancer. Cancer immunotherapy is expected to become the “fourth” cancer therapy. Cytotoxic T lymphocytes (CTL) play an essential role in immune responses to cancers, and CTL can recognize CSC/CIC in an antigen‐specific manner. CSC/CIC express several tumor‐associated antigens (TAA), and cancer testis (CT) antigens are reasonable sources for CSC/CIC‐targeting immunotherapy. In this review article, we discuss CSC/CIC recognition by CTL, regulation of immune systems by CSC/CIC, TAA expression in CSC/CIC, and the advantages of CSC/CIC‐targeting immunotherapy. Cancer stem‐like cells can be recognized by CTLs; however, CSCs/CICs inhibit naive T cell differentiation into CTLs by cytokine secretion and induction of Tregs.

Osteosarcoma (OS) is a highly malignant bone tumor and the prognosis for non‐responders to chemotherapy remains poor. Previous studies have shown that human sarcomas contain sarcoma‐initiating cells (SIC), which have the characteristics of high tumorigenesis and resistance to chemotherapy. In the present study, we characterized SIC of a novel OS cell line, screened for SIC‐related genes, and tried to regulate the proliferation of OS by metabolic interference. Initially, we established a new human OS cell line (OS13) and isolated clones showing higher tumorigenesis as SIC (OSHIGH) and counterpart clones. OSHIGH cells showed chemoresistance and their metabolism highly depended on aerobic glycolysis and suppressed oxidative phosphorylation. Using RNA‐sequencing, we identified LIN28B as a SIC‐related gene highly expressed in OSHIGH cells. mRNA of LIN28B was expressed in sarcoma cell lines including OS13, but its expression was not detectable in normal organs other than the testis and placenta. LIN28B protein was also detected in various sarcoma tissues. Knockdown of LIN28B in OS13 cells reduced tumorigenesis, decreased chemoresistance, and reversed oxidative phosphorylation function. Combination therapy consisting of a glycolysis inhibitor and low‐dose chemotherapy had antitumor effects. In conclusion, manipulation of glycolysis combined with chemotherapy might be a good adjuvant treatment for OS. Development of immunotherapy targeting LIN28B, a so‐called cancer/testis antigen, might be a good approach. Osteosarcoma‐initiating cell antigen LIN28B was expressed in sarcoma tissues. ES, epithelioid sarcoma; MFS, myxofibrosarcoma; OS, osteosarcoma; SS, synovial sarcoma.

The expression of classical human leukocyte antigen class I antigens (HLA‐I) on the surfaces of cancer cells allows cytotoxic T cells to recognize and eliminate these cells. Reduction or loss of HLA‐I is a mechanism of escape from antitumor immunity. The present study aimed to investigate the clinicopathological impacts of HLA‐I and non–classical HLA‐I antigens expressed on pancreatic ductal adenocarcinoma (PDAC) cells. We performed immunohistochemistry to detect expression of HLA‐I antigens in PDAC using 243 PDAC cases and examined their clinicopathological influences. We also investigated the expression of immune‐related genes to characterize PDAC tumor microenvironments. Lower expression of HLA‐I, found in 33% of PDAC cases, was significantly associated with longer overall survival. Higher expression of both HLA‐E and HLA‐G was significantly associated with shorter survival. Multivariate analyses revealed that higher expression of these three HLA‐I antigens was significantly correlated with shorter survival. Higher HLA‐I expression on PDAC cells was significantly correlated with higher expression of IFNG, which also correlated with PD1, PD‐L1 and PD‐L2 expression. In vitro assay revealed that interferon gamma (IFNγ) stimulation increased surface expression of HLA‐I in three PDAC cell lines. It also upregulated surface expression of HLA‐E, HLA‐G and immune checkpoint molecules, including PD‐L1 and PD‐L2. These results suggest that the higher expression of HLA‐I, HLA‐E and HLA‐G on PDAC cells is an unfavorable prognosticator. It is possible that IFNγ promotes a tolerant microenvironment by inducing immune checkpoint molecules in PDAC tissues with higher HLA‐I expression on PDAC cells. human leukocyte antigen class I antigens (HLA‐I) are needed for T cells to recognize target cells. Here, we showed that higher HLA‐I expression on pancreatic cancer cells is associated with poor prognosis, where formation of the tolerant microenvironment may be involved in IFNγ.

Adoptive T cell therapy has shown significant efficacy in cancer treatment, especially in hematologic malignancies, and is increasingly being explored for solid cancers. Combining T cell therapy with conventional treatments holds promise for enhancing therapeutic effects. In this study, we conducted an in vitro inhibitor screening to evaluate the effects of various inhibitors on T cell-mediated cytotoxic activity against cancer cells. Among the candidates, we identified afatinib as an immunosuppressive agent that attenuates T cell cytotoxic activity by reducing interferon- γ (IFN- γ ) secretion and suppressing T cell activation. Notably, this IFN- γ reduction was independent of T cell proliferation. RNA-seq analysis revealed that afatinib downregulated the T cell receptor (TCR) pathway signature. RT-qPCR demonstrated a dose-dependent suppression of IFNG mRNA expression in afatinib-treated T cells. Furthermore, afatinib impaired tumor rejection in an immunological memory mouse model that had been previously cured by anti–PD-L1 therapy, suggesting that afatinib may inhibit the function of effector memory T cells. Collectively, our findings highlight afatinib’s potential to impair T cell effector functions, indicating that strategic consideration is essential when combining epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs), including afatinib, with adoptive T cell therapies.

Photodynamic therapy (PDT) using the photosensitizer talaporfin sodium (talaporfin) is a new mode of treatment for cancer. However, the metabolic mechanism of talaporfin has not been clarified. Thus, we investigated the uptake, transportation, and elimination mechanisms of talaporfin in carcinoma and sarcoma. The results showed that talaporfin co‐localized in early endosomes and lysosomes. Talaporfin uptake was via clathrin‐ and caveolae‐dependent endocytosis and a high amount of intracellular ATP was essential. Inhibition of lysosomal enzymes maintained intracellular talaporfin levels. Inhibition of K‐Ras signaling reduced talaporfin uptake in carcinoma and sarcoma cell lines. Talaporfin was taken up by clathrin‐ and caveolae‐dependent endocytosis, translocated from early endosomes to lysosomes, and finally degraded by lysosomes. We also demonstrated that ATP is essential for the uptake of talaporfin and that activation of K‐Ras is involved as a regulatory mechanism. These results provide new insights into the metabolism of talaporfin in cancer cells for the enhancement of PDT for carcinoma and sarcoma. Intracellular talaporfin was co‐localized with early endosomes and lysosomes but not with mitochondria in osteosarcoma cells.

Background Peptide-vaccination therapy targeting tumour-associated antigens can elicit immune responses, but cannot be used to eliminate large tumour burden. In this study, we developed a therapeutic single-chain variable-fragment (scFv) antibody that recognises the cancer stem-like cell/cancer-initiating cell (CSC/CIC) antigen, DNAJB8. Methods We screened scFv clones reacting with HLA-A24:20/DNAJB8-derived peptide (DNAJB8_143) complex using naive scFv phage-display libraries. Reactivity and affinity of scFv clones against the cognate antigen were quantified using FACS and surface plasmon resonance. Candidate scFv clones were engineered to human IgG1 (hIgG1) and T-cell-engaging bispecific antibody (CD3xJB8). Complement-dependent cytotoxicity (CDC) and bispecific antibody-dependent cellular cytotoxicity (BADCC) were assessed. Results scFv clones A10 and B10 were isolated after bio-panning. Both A10-hIgG1 and B10-hIgG1 reacted with DNAJB8-143 peptide-pulsed antigen-presenting cells and HLA-A24(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. A10-hIgG1 and B10-hIgG1 showed strong affinity with the cognate HLA/peptide complex ( K D  = 2.96 × 10 −9  M and 5.04 × 10 −9  M, respectively). A10-hIgG1 and B10-hIgG1 showed CDC against HLA-A24(+)/DNAJB8(+) cell lines. B10-(CD3xJB8) showed superior BADCC to A10-(CD3xJB8). Conclusion We isolated artificial scFv antibodies reactive to CSC/CIC antigen DNAJB8-derived peptide naturally present on renal cell carcinoma and sarcoma. Immunotherapy using these engineered antibodies could be promising.

The mortality rate of oral cancer has not improved over the past three decades despite remarkable advances in cancer therapies. Oral cancers contain a subpopulation of cancer stem cells (CSCs) that share characteristics associated with normal stem cells, including self‐renewal and multi‐differentiation potential. CSCs are tumorigenic, play a critical role in cancer infiltration, recurrence, and distant metastasis, and significantly contribute to drug resistance to current therapeutic strategies, including immunotherapy. Cytotoxic CD8+ T lymphocytes (CTLs) are key immune cells that effectively recognize peptide antigens presented by the major histocompatibility complex class I molecules. Increasing evidence suggests that cancer antigen‐specific targeting by CTLs effectively regulates CSCs that drive cancer progression. In this study, we utilized data from public domains and performed various bioassays on human oral squamous cell carcinoma clinical samples and cell lines, including HSC‐2 and HSC‐3, to investigate the potential role of olfactory receptor family 7 subfamily C member 1 (OR7C1), a seven transmembrane G‐protein‐coupled olfactory receptor that is also expressed in nonolfactory tissues and was previously reported as a novel marker and target of colon cancer initiating cell‐targeted immunotherapy, in CSC‐targeted treatment against oral cancer. We found that the OR7C1 gene was expressed only in oral CSCs, and that CTLs reacted with human leukocyte antigen‐A24‐restricted OR7C1 oral CSC‐specific peptides. Taken together, our findings suggest that OR7C1 represents a novel target for potent CSC‐targeted immunotherapy in oral cancer. OR7C1 was found to be preferentially expressed in oral cancer stem cells (CSCs). OR7C1‐specific cytotoxic CD8+ T lymphocyte (CTL) clones could recognize HLA‐A24+ and OR7C1+ oral cancer cells and specifically lyse oral CSCs. The results indicate that OR7C1 is a reasonable candidate for treatment‐resistant CSC.

We developed an immunohistogram representing an individual cancer-immunity cycle based on immunohistochemical analyses. We evaluated its ability to predict the efficacy of immune checkpoint inhibitors (ICI) in 11 patients with urothelial carcinoma and 7 patients with renal cell carcinoma who underwent surgery and received ICIs for disease recurrence. Immunohistochemical analyses for CD8, TIA-1, HLA class I, HLA-DR, and PD-L1 were performed and scored 0–3. T-cell infiltration pattern was classified into desert, excluded, partially inflamed, and inflamed. Tumors with an inflamed or partially inflamed pattern and positive scores (score ≥ 1) for all five immune markers were classified as “immune-hot” and others as “immune-cold.” Association between the immunohistogram and ICI treatment efficacy was evaluated with objective response rate, disease control rate (DCR), progression-free survival (PFS), and cancer-specific survival (CSS). Eight (44%) and 10 (56%) patients had immune-hot and immune-cold tumors, respectively. Immune-hot tumors showed a higher DCR (100% vs. 40%, p  < 0.01), longer PFS (median unreached for hot, 1.3 months for cold, p  < 0.01), and longer CSS (median unreached for hot, 3.3 months for cold, p  < 0.01) than immune-cold tumors. The immunohistogram could be clinically useful as an accessible biomarker for precision cancer immunotherapy in urological cancer.