Natalie Gonzalez

Introduction

The leading cause of cancer deaths is attributed to lung cancer, with 80% of all cases associated with non–small cell lung cancer (NSCLC).^1,2 One therapy currently being used is anti-PD-1/PD-L1 monotherapy.¹ However, the tumor microenvironment (TME) of hypoxia and hyperangiogenesis, caused by overexpression of vascular endothelial growth factor A (VEGFA), contributes to immunosuppression in lung cancer patients, leading to a decreased response to this therapy.³ To reduce immunosuppression in the TME and to improve the efficacy of PD-1/PD-L1 blockade treatments, the abnormal vasculature of the tumor should be targeted by using anti-angiogenic factors, such as low dose apatinib.^1,3,4

Methods

In Zhao et al., male mice were tested for two types of tumor models: subcutaneous and metastasis. Apatinib treatment at various doses was administered orally every day, 3 days after tumor cell inoculation, and Anti–PD-L1 was administered every 3 days. Tissues from tumor-bearing mice were harvested for analysis and measurement at indicated days. Flow cytometry analysis, histologic analysis, and cytokine assay were then performed.¹ In Wang et al., cell lines were infected with lentivirus supernatant and analyzed via quantitative real-time PCR and Western blot. Tumor models were evaluated for control and VEGFA overexpression, and different treatments (apatinib and anti-PD-1 antibody) were administered to different groups. The tumors were analyzed by immunohistochemistry, immunofluorescence, RNA sequencing and analysis, and flow cytometry.⁴

Results

In Zhao et al., combination therapy with low dose apatinib lowered factors such as hypoxia inducible factor 1 (HIF1), showing an improvement in hypoxic conditions. There was also increased amount of infiltrating CD8+ T cells, reduced tumor-associated macrophages, and decreased serum and tumor TGFβ amounts.¹ In Wang et al., mouse models also showed reduced metastases, stunted tumor growth, and prolonged survival in mice with NSCLC when co-administering the anti-PD-1 with low dose apatinib. However, the combination only improved treatment outcomes in mice with overexpression of VEGFA and not in mice without overexpression.⁴

Conclusion

PD-1-PD-L1 is a mechanism for tumor immune resistance that can be an important target for reduction of tumors in NSCLC patients, with low efficacy due to immunosuppressive TME.⁵ This can be improved by combining the blockade with low dose apatinib, which improves hypoxic conditions of the TME increases antitumor efficacy. However, this combination therapy is only effective in patients with overexpressed VEGFA. Therefore, it is important to investigate whether tumors have hypervascularization and an overexpression of VEGFA before administering a combination of anti-PD-1 and apatinib.^6-8

References

1. Zhao S, Ren S, Jiang T, et al. Low-Dose Apatinib Optimizes Tumor Microenvironment and Potentiates Antitumor Effect of PD-1/PD-L1 Blockade in Lung Cancer. Cancer Immunol Res. Apr 2019;7(4):630-643. doi:10.1158/2326-6066.CIR-17-0640
2. Duma N, Santana-Davila R, Molina JR. Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment. Mayo Clin Proc. Aug 2019;94(8):1623-1640. doi:10.1016/j.mayocp.2019.01.013
3. Koh YW, Lee SJ, Han JH, Haam S, Jung J, Lee HW. PD-L1 protein expression in non-small-cell lung cancer and its relationship with the hypoxia-related signaling pathways: A study based on immunohistochemistry and RNA sequencing data. Lung Cancer. Mar 2019;129:41-47. doi:10.1016/j.lungcan.2019.01.004
4. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. Jan 24 2018;553(7689):446-454. doi:10.1038/nature25183
5. Mitsuhashi A, Kondoh K, Horikawa K, et al. Programmed death (PD)-1/PD-ligand 1 blockade mediates antiangiogenic effects by tumor-derived CXCL10/11 as a potential predictive biomarker. Cancer Sci. Dec 2021;112(12):4853-4866. doi:10.1111/cas.15161
6. Altorki NK, Markowitz GJ, Gao D, et al. The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer. Jan 2019;19(1):9-31. doi:10.1038/s41568-018-0081-9
7. Wang Q, Gao J, Di W, Wu X. Anti-angiogenesis therapy overcomes the innate resistance to PD-1/PD-L1 blockade in VEGFA-overexpressed mouse tumor models. Cancer Immunol Immunother. Sep 2020;69(9):1781-1799. doi:10.1007/s00262-020-02576-x
8. Chen D, Wang Y, Zhang X, et al. Characterization of Tumor Microenvironment in Lung Adenocarcinoma Identifies Immune Signatures to Predict Clinical Outcomes and Therapeutic Responses. Front Oncol. 2021;11:581030. doi:10.3389/fonc.2021.581030