Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine increased pancreatic cancer cells\' HLA-I mRNA transcripts, total protein, surface expression, and surface stability. Temperature-dependent assay results indicated that the increased HLA-I stability may be due to reduced binding of low affinity peptides. Mass spectrometry analysis confirmed changes in the HLA-I-presented peptide pool post-treatment, and computational predictions suggested improved affinity and immunogenicity of peptides displayed solely by gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were derived from unique source proteins, with a notable overrepresentation of translation-related proteins. Gemcitabine also increased expression of select immunoproteasome subunits, providing a plausible mechanism for its modulation of the HLA-I-bound peptidome. Our work supports continued investigation of immunotherapies, including peptide-based vaccines, to be used with gemcitabine as new combination treatment modalities for pancreatic cancer.

UNASSIGNED: An effective salvage regimen for the reinduction of remission is lacking for refractory or relapsed primary central nervous system lymphoma (r/r PCNSL). This study aimed to evaluate the efficacy and safety of cytarabine plus temozolomide in treating r/r PCNSL and to explore the associated prognostic factors.
UNASSIGNED: A single-center retrospective cohort study was conducted to assess the efficacy and safety of cytarabine and temozolomide (AT) in r/r PCNSL patients. KIR and HLA genotyping was performed on peripheral blood samples.
UNASSIGNED: Thirty PCNSL patients receiving an AT regimen (cytarabine 3 g/m2 for 2 days combined with temozolomide 150 mg/m2 for 5 days) in our institution were analyzed. The median age was 65 years (range 25-79 years). A total of 43.4% of patients (13/30) achieved an overall response within a median follow-up of 16 months (95% confidence interval [CI]: 11-23 months). The median PFS and OS of the cohort were 1.5 months (95% CI: 1-4 months) and 19.5 months (95% CI: 11 months to not calculable), respectively. Patients harboring KIR3DL1/HLA-B genotypes predicting low affinity had a higher response rate (p = 0.042) and longer median PFS (3 months) than those with KIR3DL1/HLA-B genotypes predicting high affinity (1 month) (p = 0.0047). Cox regression analysis indicated that KIR/HLA-B genotypes were independently associated with PFS (p = 0.043). However, KIR/HLA-B genotypes had no impact on the OS of the cohort. The toxicity of AT treatment was mild and manageable.
UNASSIGNED: The AT regimen was well tolerated, and patients with specific KIR-HLA genotypes may benefit from this regimen.

OBJECTIVE: The prognosis of recurring and metastatic head and neck squamous cell carcinoma (HNSCC) is poor. Although immune checkpoint inhibitors have expanded the treatment options for HNSCC, the response rates are low. Alternatively, cancer vaccines and T-cell therapies are being developed. Identification of useful common cancer antigens and confirmation of human leukocyte antigen (HLA) class I expression are required.
METHODS: Immunohistochemistry analyses were performed for 10 antigens (FOXM1, TGFBI, SPARC, HSP105α, WT1, AFP, GPC3, PP-RP, KIF20A, KM-HN-1) and HLA class I using specimens of 56 surgical cases. Staining intensity, percentage of stain-positive areas, and localization of staining in the tumor cells and normal tissue were evaluated.
RESULTS: Staining of FOXM1, TGFBI, SPARC, and HSP105α was more predominant in tumor cells than that in normal cells. The expression rates of these antigens in tumor cells were 60.7%, 58.9%, 73.2%, and 50.0%, respectively. Regarding sites, the expression rates of these antigens in oral cancer were high at 57.1%, 71.4%, 81.0%, and 66.7%, respectively. Furthermore, the expression of HLA class I was 83.9% in all cases. Of these, 68.1% showed expression on the plasma membrane.
CONCLUSIONS: FOXM1, TGFBI, SPARC, and HSP105α could be useful common cancer antigens, and HLA class I is expressed on the plasma membrane of cancer cells in many cases. The results suggest that cancer vaccines and T-cell therapy may be clinically viable options for HNSCC treatment.

Immune checkpoint inhibitors (ICIs) have dramatically improved the outcomes of non-small cell lung cancer patients and have increased the possibility of long-term survival. However, few patients benefit from ICIs, and no predictive biomarkers other than tumor programmed cell death ligand 1 (PD-L1) expression have been established. Hence, the identification of biomarkers is an urgent issue. This review outlines the current understanding of predictive markers for the efficacy of ICIs, including PD-L1, tumor mutation burden, DNA mismatch repair deficiency, microsatellite instability, CD8+ tumor-infiltrating lymphocytes, human leukocyte antigen class I, tumor/specific genotype, and blood biomarkers such as peripheral T-cell phenotype, neutrophil-to-lymphocyte ratio, interferon-gamma, and interleukin-8. A tremendous number of biomarkers are in development, but individual biomarkers are insufficient. Tissue biomarkers have issues in reproducibility and accuracy because of intratumoral heterogeneity and biopsy invasiveness. Furthermore, blood biomarkers have difficulty in reflecting the tumor microenvironment and therefore tend to be less predictive for the efficacy of ICIs than tissue samples. In addition to individual biomarkers, the development of composite markers, including novel technologies such as machine learning and high-throughput analysis, may make it easier to comprehensively analyze multiple biomarkers.

Pancreatic cancer is one of the deadliest neoplasms, with a dismal 5-year survival rate of only 10%. The ability of pancreatic cancer cells to evade the immune system hinders an anti-tumor response and contributes to the poor survival rate. Downregulation of major histocompatibility complex (MHC) class I cell-surface expression can aid in immune evasion by preventing endogenous tumor antigens from being presented to cytotoxic T cells. Earlier studies suggested that epidermal growth factor receptor (EGFR) signaling can decrease MHC class I expression on certain cancer cell types. However, even though erlotinib (a tyrosine kinase inhibitor that targets EGFR) is an approved drug for advanced pancreatic cancer treatment, the impact of EGFR inhibition or stimulation on pancreatic cancer cell MHC class I surface expression has not previously been analyzed. In this current study, we discovered that EGFR affects MHC class I mRNA and protein expression by human pancreatic cancer cell lines. We demonstrated that cell-surface MHC class I expression is downregulated upon EGFR activation, and the MHC class I level at the surface is elevated following EGFR inhibition. Furthermore, we found that EGFR associates with MHC class I molecules. By defining a role in pancreatic cancer cells for activated EGFR in reducing MHC class I expression and by revealing that EGFR inhibitors can boost MHC class I expression, our work supports further investigation of combined usage of EGFR inhibitors with immunotherapies against pancreatic cancer.

Human papillomavirus (HPV)-related cancer is one of the diseases entities for which the applications of radiotherapy have been increasing. Recently, the process of carcinogenesis from HPV infection and the mechanism of tumor immunity that develops during disease progression have been elucidated. In this review, we will describe the mechanism of tumor immunity and how chemoradiotherapy may overcome and improve the efficacy of tumor immunity. We will also discuss the usefulness of proteins involved with tumor immunity as a predictive marker of radiotherapy response, and present an overview of ongoing clinical trials of combinations of immune checkpoint inhibitors and radiotherapy to demonstrate the promising combination therapy that has been currently emerging.

To supplement clinical decision-making in the management of cervical cancer, various prognostic factors, including tumor immune microenvironments, were examined in patients with cervical cancer treated with definitive chemoradiotherapy. We retrospectively analyzed the expression of CD8, FoxP3, HLA-1, PD-L1, and XRCC4 in 100 cases of cervical cancer. The observed tumor immune microenvironments were also classified into three types: inflamed, excluded, and cold type. Less FoxP3+ T cells and cold-type tumor were found to be poor prognostic factors in addition to non-SCC, large pre-treatment tumor volume, and three or less cycles of concurrent chemotherapy based on multivariate analysis. Cold-type tumors had significantly worse prognoses than the other two types, whereas inflamed- and excluded-type tumors showed similar 5-year disease-specific survival (P < 0.001; 0% vs. 60.3% vs. 72.3%). Radiotherapy could overcome the inhibitory immune microenvironment that occurs in excluded type. Individualized combination therapy adapted to pre-treatment tumor immunity may be necessary to improve radiotherapy outcomes in cervical cancer.

Limited clinical application of antibody-drug conjugates (ADCs) targeting tumor associated antigens (TAAs) is usually caused by on-target off-tumor side effect. Tumor-specific mutant antigens (TSMAs) only expressed in tumor cells which are ideal targets for ADCs. In addition, intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I (HLA I)molecules forming tumor-specific peptide/HLA I complexes. KRAS G12V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy. In this study, we generated two TCR-mimic antibody-drug conjugates (TCRm-ADCs), 2E8-MMAE and 2A5-MMAE, targeting KRAS G12V/HLA-A*0201 complex, which mediated specific antitumor activity in vitro and in vivo without obvious toxicity. Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs, which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.

Downregulation of human leukocyte antigen (HLA) class I has been postulated to be a mechanism of adaptive immune escape in various tumors, especially microsatellite instability-high (MSI-H) colorectal cancer (CRC). In this study, we aimed to investigate HLA class I and β2-microglobulin (β2M) expression in MSI-H and microsatellite-stable (MSS) CRCs and determine its prognostic impact. The representative areas from the tumor center (TC) and tumor periphery (TP) from 300 CRCs, including 161 MSI-H and 139 MSS cases, were selected to construct a tissue microarray. Immunohistochemistry (IHC) for HLA A/B/C, β2M, CD3, and CD8 was performed. Reduced HLA A/B/C expression was detected in 113 (70.2%) MSI-H and 54 (38.8%) MSS cases, while reduced β2M expression was observed in 69 (42.9%) MSI-H and 17 (12.2%) MSS cases. Although reduced β2M expression was associated with higher pathological tumor (pT) stage in MSI-H CRC with borderline significance, no association was found between HLA A/B/C and β2M expression and survival. Interestingly, reduced HLA A/B/C expression in MSS was associated with higher stage, and reduced HLA A/B/C and β2M expression was an independent prognostic factor in multivariate analysis. In conclusion, reduced HLA A/B/C and β2M expression was frequently observed in immunotherapy-naive MSI-H CRC, suggesting the possibility of primary resistance to immune checkpoint inhibitor. Interestingly, downregulation of HLA A/B/C and β2M was associated with poor prognosis in MSS cancers. Overall, IHC for HLA A/B/C and β2M might be a feasible predictive or prognostic tool in CRC.

OBJECTIVE: To evaluate proteins related to tumor immune response and treatment outcome from radiotherapy for uterine cervical cancer patients.
METHODS: We performed a retrospective immunohistochemical staining of 81 patients with uterine cervical cancer who underwent definitive radiotherapy. We examined the expression of programmed death ligand 1, human leukocyte antigen class I, tumor-infiltrating CD8+, and forkhead box P3+ (FoxP3+) T cells in tumor tissues.
RESULTS: In biopsy specimen, patients with a higher number of CD8+ T cells and FoxP3+ T cells had a better disease-specific survival than patients with a lower number of CD8+ T cells and FoxP3+ cells (P = 0.018 and P = 0.009). Multivariate analysis showed that equivalent dose in 2 Gy fractions (EQD2) of the minimum dose to 90% of the high-risk clinical target volume, FoxP3+ T cells and expression of human leukocyte antigen class I were significant prognostic factors. When the EQD2 is 70 Gy or more, a higher local control rate is obtained regardless of the number of CD8- or FoxP3-positive cells. When EQD2 is <70 Gy, the number of CD8-positive cells has a significant impact on treatment outcome: the recurrence rate (local recurrence rate + distant metastasis rate) was 46.2% in the group with a CD8 value of 230 or higher, whereas the recurrence rate was 75.7% in the group with a CD8 value of less than 230.
CONCLUSIONS: The combination of CD8 or FoxP3 with EQD2 can be potentially useful to predict the treatment results of radiotherapy for cervical cancer, leading to individualized optimal selection of treatment for cervical cancer.