Haishan Lin

Background/Objectives: Cancer is the second leading cause of death globally, and resistance to immunotherapy requires new strategies. One promising approach is cross-line immunotherapy, defined as retreatment with the same or different immune checkpoint inhibitors after progression on prior immunotherapy. Understanding the efficacy and safety of this innovative treatment modality is critical for advancing cancer care. Methods: In this study, we evaluated outcomes of cross-line immunotherapy in a cohort of 105 patients with various malignant tumors at Beijing Friendship Hospital. The primary endpoints of the study included progression-free survival (PFS2) and overall survival (OS), measured from the initiation of cross-line immunotherapy. All patients received treatment regimens determined by their physicians. The study aimed to evaluate the efficacy of cross-line immunotherapy, with or without other therapies. Results: The study reported a median PFS2 of 6.9 months (95% CI: 4.7–8.1) and a median OS of 12.9 months (95% CI: 11.7–NA). The objective response rate (ORR) was 11%, while the disease control rate (DCR) was 77%. Although 35.2% of patients experienced grade 3 or higher immune-related adverse events, primarily hematological toxicities, no specific immune treatment-related hematological events were noted. Additionally, elevated D-dimer levels and hyponatremia emerged as prognostic factors associated with poorer outcomes, whereas hypertriglyceridemia correlated with enhanced survival. A nomogram developed for predicting PFS2 and OS demonstrated high discriminative capacity. Conclusions: These findings show that cross-line immunotherapy is safe and effective for patients with malignant tumors. It offers a viable option for patients who are progressing after initial treatments, which highlights the need for personalized strategies.

Introduction. Immunotherapy is currently the most promising antitumor treatment approach. However, the colon cancer immunotherapy indication dMMR/MSI-H do not cover all colon cancer patients suitable for immunotherapy. We performed transcriptome-wide expression profile analyses of pMMR/MSS colon adenocarcinoma (COAD) specimens from TCGA database to identify a genetype signature associated with tumor immune microenvironment types (TIMTs). Methods. TCGA database was used to identify tumor genotypes suitable for antitumor immunotherapy. We analyzed RNA-sequencing profiles of 338 COAD targeted to the pMMR/MSS group from TCGA public dataset. The ESTIMATE and the CIBERSORT were used to analyze the pMMR/MSS COAD immune microenvironment between APC wild and APC mutation. Furthermore, we further verified the relationship between APC genotype and TIMTs and the efficacy of immunotherapy in 42 colon cancer specimens. Results. We identified that in APC-wt/MSS colon cancer, the expressions of PD-1, PD-L1, CTLA4, and CYT (GZMA and PRF1) were increased. The TMB, Immunoscore, and the proportion of CT8+ T cell infiltration also were identified increasing in these patients. And pathway enrichment analysis for differentially expressed genes (DEGs) between APC-wt and APC-mt MSS COAD was done to further explore their biological function. Similarly, the significant pathways for DEGs were mainly enriched in the immune response, extracellular matrix, and cell adhesion which involved in immune response. Specimens from 42 colon cancer patients, including 22 APC-mt/MSS and 20 APC-wt/MSS, were immunohistochemically evaluated for expression of CD8 and PD-L1. And APC-wt/MSS tumors showed significantly higher expression of CD8 and PD-L1 than APC-mt/MSS tumor. Moreover, APC-wt was compared with APC-mt MSS/pMMR colon cancer (DOR, 45% and 26.7%, respectively; ). Conclusion. Based on the results, we found that more colon cancers of APC-wt/MSS are classified by TMIT I. And APC-wt/MSS colon cancer patients are more likely to benefit from antitumor immunotherapy.

Summary: Background: The corona virus disease 2019 (COVID-19) pandemic poses a severe challenge to public health, especially to those patients with underlying diseases. In this meta-analysis, we studied the prevalence of cancer among patients with COVID-19 infection and their risks of severe events. Methods: We searched the Pubmed, Embase and MedRxiv databases for studies between December 2019 and May 3, 2020 using the following key words and terms: sars-cov-2, covid-19, 2019-ncov, 2019 novel coronavirus, corona virus disease-2019, clinical, clinical characteristics, clinical course, epidemiologic features, epidemiology, and epidemiological characteristics. We extracted data following PICO (patient, intervention, comparison and outcome) chart. Statistical analyses were performed with R Studio (version 3.5.1) on the group-level data. We assessed the studies’ risk of bias in accordance to the adjusted Joanna Briggs Institute. We estimated the prevalence or risks for severe events including admission into intensive care unit or death using meta-analysis with random effects. Findings: Out of the 2,551 studies identified, 32 studies comprising 21,248 participants have confirmed COVID-19. The total prevalence of cancer in COVID-19 patients was 3.97% (95% CI, 3.08% to 5.12%), higher than that of the total cancer rate (0.29%) in China. Stratification analysis showed that the overall cancer prevalence of COVID-19 patients in China was 2.59% (95% CI, 1.72% to 3.90%), and the prevalence reached 3.79% in Wuhan (95% CI, 2.51% to 5.70%) and 2.31% (95% CI, 1.16% to 4.57%) in other areas outside Wuhan in China. The incidence of ICU admission in cancer patients with COVID-19 was 26.80% (95% CI, 21.65% to 32.67%) and the mortality was 24.32% (95% CI, 13.95% to 38.91%), much higher than the overall rates of COVID-19 patients in China. The fatality in COVID patients with cancer was lower than those with cardiovascular disease (OR 0.49; 95% CI, 0.34 to 0.71; p=0.39), but comparable with other comorbidities such as diabetes (OR 1.32; 95% CI, 0.42 to 4.11; p=0.19), hypertension (OR 1.27; 95% CI, 0.35 to 4.62; p=0.13), and respiratory diseases (OR 0.79; 95% CI, 0.47 to 1.33; p=0.45). Interpretation: This comprehensive meta-analysis on the largest number of patients to date provides solid evidence that COVID-19 infection significantly and negatively affected the disease course and prognosis of cancer patients. Awareness of this could help guide clinicians and health policy makers in combating cancer in the context of COVID-19 pandemic. Funding: Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202010025047).

Aims: Pyrotinib is a newly developed irreversible pan-ErbB receptor tyrosine kinase inhibitor for treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers, and clinic trials of pyrotinib in treatment of HER2-positive gastric cancer (GC) are underway. Exosomes are tiny vesicles secreted by cancer cells and take essential roles in the progression of carcinoma. Whether pyrotinib application has any effect on the cancer cell-released exosomes has not been studied. The aim of our work was to address if pyrotinib treatment impacts the effect of HER2-positive GC cell-derived exosomes on endothelial cell (EC) progression. Methods: Isolation of exosomes released by HER2-positive NCI-N87 and MKN45 lines after pyrotinib treatment was performed. Then, human umbilical vein endothelial cells (HUVECs) were incubated with different concentrations of exosomes to address their proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). Effect of pyrotinib-treated exosomes at concentration of 10 μg/mL was compared to that without pyrotinib treatment over 96-hr time course. Transwell assay and wound-healing assay were carried out by incubating with exosomes released by NCI-N87 and MKN45 cells with/without pyrotinib treatment over 24-hr time course. The aforementioned experiments were done under same conditions in order to evaluate the combined effect of apatinib and pyrotinib on HUVEC motility and invasive capacity. Results: We showed that HUVEC proliferation, motility and invasive capacity were further enhanced upon incubation with exosomes released by pyrotinib-treated GC cell lines, compared to those without pyrotinib treatment. Significantly, this effect was counteracted by the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor apatinib which inhibits EC progression. Conclusion: Our study suggests that pyrotinib application on HER2-positive GC produces stronger exosomes that promote the proliferation and motility of vascular ECs, and combination of pyrotinib with apatinib provides potentially better therapy.

CSF-1 or IL-34 stimulation of CSF1R promotes macrophage differentiation, activation and osteoclastogenesis, and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis. The objective of this study was to determine the relative contributions of CSF-1 and IL-34 signaling to CSF1R in RA. CSF-1 and IL-34 were detected by immunohistochemical and digital image analysis in synovial tissue from 15 biological-naïve rheumatoid arthritis (RA) , 15 psoriatic arthritis (PsA) and 7 osteoarthritis (OA) patients . Gene expression in CSF-1- and IL-34-differentiated human macrophages was assessed by FACS analysis and quantitative PCR. RA synovial explants were incubated with CSF-1, IL-34, control antibody (Ab), or neutralizing/blocking Abs targeting CSF-1, IL-34, or CSF1R. The effect of a CSF1R-blocking Ab was examined in murine collagen-induced arthritis (CIA). CSF-1 (also known as M-CSF) and IL-34 expression was similar in RA and PsA synovial tissue, but lower in controls (P < 0.05). CSF-1 expression was observed in the synovial sublining, and IL-34 in the sublining and the intimal lining layer. CSF-1 and IL-34 differentially regulated the expression of 17 of 336 inflammation-associated genes in macrophages, including chemokines, extra-cellular matrix components, and matrix metalloproteinases. Exogenous CSF-1 or IL-34, or their independent neutralization, had no effect on RA synovial explant IL-6 production. Anti-CSF1R Ab significantly reduced IL-6 and other inflammatory mediator production in RA synovial explants, and paw swelling and joint destruction in CIA. Simultaneous inhibition of CSF1R interactions with both CSF-1 and IL-34 suppresses inflammatory activation of RA synovial tissue and pathology in CIA, suggesting a novel therapeutic strategy for RA.

IL-34 is a newly identified cytokine that binds to the CSF-1 receptor (CSF-1R), promotes monocyte viability, and stimulates macrophage colony formation (Lin et al., 2008). Here we demonstrate that human IL-34 induced tyrosine phosphorylation of the CSF-1R in cells of a mouse MacCsf1r−/−.huCSF-1R macrophage line. MacCsf1r−/−.huCSF-1R cells were obtained by retroviral transduction of the human CSF-1R into cells of the MacCsf1r−/− macrophage line (Yu et al., 2008) derived from bone marrow macrophages isolated from a CSF-1R-deficient mouse. In addition, IL-34 stimulated the downstream signaling of ERK1/2 and the IL-34-induced phosphorylation of ERK1/2 was blocked by a CSF-1R-specific inhibitor. IL-34, in synergy with RANK ligand, promoted formation of tartrate resistant acid phosphatase (TRAP)-positive and multinucleated osteoclasts from monocytes in dose-dependent manner. The activity of IL-34 on osteoclast differentiation was inhibited by the soluble CSF-1R extracellular domain. Therefore, IL-34 functions as a new ligand of CSF-1R and participates in the regulation of osteoclast development.