2205P - Tumor-infiltrating lymphocytes score possesses a relation with adjuvant chemo-immunotherapy benefit and cellular morphology in large-cell neuroendocrine carcinoma

Background

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of lung cancer with a worse prognosis. The benefit of adjuvant chemotherapy (aCT) or immunotherapy is controversial. Hence, effective biomarkers for selecting sensitive patients after surgery are urgently needed. Microenvironmental morphological fluctuations affect gene regulation and facilitate nuclear transport, finally changing immunity interaction. However, little is known in LCNEC.

Methods

Here, 190 LCNECs were reviewed, and 53 postoperative stage II and III LCNECs with and without aCT were evaluated for CD4+ T, CD8+ T, CD3, PD-1, and PD-L1 expression by IHC. Cellular morphology was described via machine learning algorithms in H&E staining slides.

Results

In patients who received aCT, high expression of CD3 and CD4 had a better OS, while CD8 could not separate aCT benefit. There was no survival difference between aCT and surgery alone in whole cohort. However, in CD4 or CD3 high expression group, patients receiving aCT exhibited longer OS than those undergoing surgery alone. A T cell stratification (CD3CD4 score) was developed to identify aCT-sensitive patient. CD3CD4 score>0 group could benefit from aCT, while CD3CD4 score=0 group might suffer from aCT toxic effect. Moreover, PD-L1 low expression patients from CD3CD4 score>0 group survive better than others in aCT arm. CD3CD4 score possessed a superior prognosis predictive performance than other clinicopathological factors. Histology-based Digital-Staining segmented 45639 six-type cells' morphological characteristics from tumor cell, lymphocyte, stroma cell, red blood cell, macrophage, and karyorrhexis. CD3CD4 score>0 group had more lymphocytes but was scant in red blood cell. Interestingly, the nucleic size and shape of tumor cell, lymphocyte, stroma cell, and macrophage were all dramatically smaller than CD3CD4 score=0 group.

Conclusions

Our results implicated stage II-III LCNEC with high CD3+ and CD4+ cell infiltration could benefit from aCT and PD-L1 blockade, highlighting the potential role of rare tumor microenvironment cellular morphological characteristics in chemo-immunotherapy sensitivity and surgery prognosis.

Clinical trial identification

Researchregistry8601; December 29, 2022.

Editorial acknowledgement

All authors would like to thank the specimen donors used in this study. Thank Afu Shixiong from The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology for his guide in pathology evaluation review. Thank Chaju Lin, Dehua Luo, Xingang Bi, and Chen Lulu Shijie for sharing experiment experience.

Legal entity responsible for the study

H. Zhao, X. Bi, Z. Luo.

Funding

This work was supported by National Natural Science Foundation of China (82141127, 82002610, 82002432); CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-C&T-B-043, 2021-I2M-C&T-B-052, 2020-I2M-C&T-B-071); Beijing CSCO Clinical Oncology Research Foundation (Y-XD202001-0111, Y-2019AZMS-0082, Y-XD202002-0370); Beijing Natural Science Foundation (J20010); Fundamental Research Funds for the Central Universities (No. 3332022029); Zhiwen Luo was awarded a funding for research in Israel (China Scholarship Council No. 202106210312).

Disclosure

All authors have declared no conflicts of interest.