Further Understanding of Immune Mechanisms in Tumor Microenvironment Is Key to Advancing Immunotherapy in Solid Tumors

Lieping Chen, MD, PhD

Although the immune system plays a vital role in attacking tumor cells, the immune mechanisms vary from tumor to tumor, and factors in the tumor microenvironment can reduce the effectiveness of the body’s immune response, according to Lieping Chen, MD, PhD.

“When tumors start growing in the body, then you have the immune system [being] alerted. This allows the priming of T cells,” Chen said in a presentation at the 16th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies.¹ “When those T cells eventually mature and become effector cells, which are really the final killer cells, they arrive in the tumor site, recognize tumor energy, and then kill the tumor.”

As T cells continue to mature, they will also release a cytokine called interferon gamma, which, among other purposes, serves as a signal between tissues and the immune system, allowing the immune response to grow stronger, Chen explained. Interferon gamma was also found to upregulate a molecule that researchers initially deemed B7-H1, which is now commonly referred to as PD-L1.²

“PD-L1 is upregulated on the surface of a variety of different types of cells, including tumor cells,” said Chen, who is the United Technologies Corporation Professor in Cancer Research and a professor of Immunobiology, of Dermatology, and of Medicine (Medical Oncology) at the Yale School of Medicine in New Haven, Connecticut.

“When more T cells come in and try to encounter these tumor cells, try to kill tumor cells, [interferon gamma] will deliver a signal through PD-1 to T cells and basically induce [cell] death or dysfunction of T cells.”

Chen added that this pathway can disrupt the immune response and shut down T cells in the immune microenvironment. Hence, blocking this interaction is thought to preserve the immune response.

Since the discovery of PD-L1’s potential role in tumor immune response, investigators have shown that:

1. Tumor-infiltrating lymphocytes (TILs) are required for an immune response, but their presence is not singularly sufficient;
2. PD-1 expression is unlikely a limiting factor since TILs are primarily PD-L1 positive;
3. PD-L1 is mainly an inducible protein, suggesting negative feedback;
4. Tumor antigen recognition in the tumor microenvironment is required;
5. Since PD-L1 expression is highly heterogenic, only certain spots on a tumor will have upregulated PD-L1; and
6. Cold tumors would not benefit from anti–PD-1/L1 therapy.

As research has continued, investigators have expanded their knowledge on the overall immune response to tumors and where PD-L1 fits into the picture. “Immune therapy is getting to a new era of [understanding] the tumor microenvironment,” Chen said. “What we found is the immune response [is] highly localized in the tumor site and manipulating that and suppressing the tumor site is critical.”

Investigators created a TIME (tumor immunity in microenvironment) classification for human cancer.³ Tissue samples were used to conduct a biomarker analysis with CD3 staining to identify TILs and PD-L1 staining. Tumors are then classified into 1 of 4 categories, including double negative for TILs and PD-L1, double positive for TILs and PD-L1, TIL positive, or PD-L1 positive.

Across multiple studies of various solid tumors, including melanoma, lung cancer, bladder cancer, renal cell carcinoma, colorectal cancer, gastric cancer, breast cancer, and triple-negative breast cancer, tissue sample were collected from 2453 patients, and the double-negative, double-positive, TIL-positive, and PD-L1–positive rates were 41%, 23%, 25%, and 11%, respectively.

“[Breaking] this down to these 4 different categories gives us the opportunity to understand the mechanism, what is behind this, and to discover the target [to] further the therapy for different types of tumors."

Chen expanded by pointing out that double-negative tumors and PD-L1–positive tumors are considered cold tumors, since TILs do not infiltrate into the tumor.⁴ Double-positive and TIL-positive tumors are considered hot. Those tumors that are double positive can be treated with anti–PD-1/L1 therapy, and TIL-positive tumors are candidates for other inhibitors, Chen noted.

A variety of data are available detailing the reason a tumor could be considered cold, Chen continued, including a lack of innate immunity, a chemical or biochemical barrier such as hypoxia or aberrant metabolism, a physical barrier such as abnormal vasculature or fibrosis, or impaired T-cell mobility.

The CD93/IGFBP7 Axis and Abnormality of Tumor Vasculature

Researchers sought to identify pathways associated with abnormal tumor vasculature in solid tumors, and they identified an interaction between insulin-like growth factor binding protein 7 (IGFBP7) and its receptor CD93.⁵ A transcriptome analysis found that IGFBP7 was highly upregulated in tumor vasculature, and a bioinformatic analysis showed a strong association of CD93 message with less TILs in human cancer.

“These two molecules [interact], which actually keeps the tumor vasculature in very tight conditions, which prevents the immune cells from getting in the tumor tissue,” Chen said.

High levels of IGFBP7 RNA expression can be found in the kidney, heart, liver, gallbladder, thyroid, and muscle. However, IGFBP7 protein is found at low levels in those tissues and normal epithelial cells, and it is frequently upregulated on endothelial cells in the tumor microenvironment. Functions of IGFBP7 include mammary gland development and endothelial cell angiogenesis.

CD93, which is primarily expressed in endothelial cells, immature B cells, and monocytes, has been reported to play important roles in vascular angiogenesis. Researchers showed that CD93 and IGFBP7 were upregulated in tumor-associated endothelial cells.

In two mouse models, the use of monoclonal antibodies to block the interaction between CD93 and IGFBP7 promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion.

Additionally, CD93 blockade in mice increased drug delivery, producing an improved antitumor response to gemcitabine or fluorouracil, and generated a substantial increase in intratumoral effector T cells to sensitize mouse tumors to immune checkpoint inhibition.

Notably, an analysis of samples from patients with cancer receiving anti–PD-1/L1 therapy showed that overexpression of the IGFBP7/CD93 pathway was associated with poor response.

Chen noted that the anti-CD93 monoclonal antibodies DCBY02 and DCSZ11 are under investigation in a phase 1 trial (NCT05496595) in patients with advanced or metastatic solid tumors.

Editor’s note: In the past 12 months, Dr Chen reported being a scientific founder of NextCure, DynamiCure, Tcelltech, and Normunity; being a consultant, board member, observer, or scientific advisory board member at NextCure, Tcelltech, Normunity, DynamiCure, Junshi, Zai Lab, and OncoC4; and had sponsored research through NextCure, DynamiCure, and Normunity.

References

1. Chen L. Challenges in immunotherapy of urological cancers. Presented at: 16th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies; March 10-11, 2023. New York, NY.
2. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365-1369. doi:10.1038/70932
3. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19(5):1021-34. doi:10.1158/1078-0432.CCR-12-2063
4. Kim TK, Vandsemb EN, Herbst RS, Chen L. Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities. Nat Rev Drug Discov. 2022;21(7):529-540. doi:10.1038/s41573-022-00493-5
5. Sun Y, Chen W, Torphy RJ, et al. Blockade of the CD93 pathway normalizes tumor vasculature to facilitate drug delivery and immunotherapy. Sci Transl Med. 2021;13(604):eabc8922. doi:10.1126/scitranslmed.abc8922