Differences immune microenvironment of various tumors

Differences immune microenvironment of various tumors. The difference in the immune microenvironment of different tumors determines the effect of immunotherapy.

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The tumor microenvironment contains a complex population of cells: tissue-resident lymphocytes, fibroblasts, endothelial cells and neurons, etc., which are formed before tumor formation, and blood-derived cells are recruited to the tumor site, each type of cell may Both are involved in the progression of the tumor.

Different tumors have different cellular components in the tumor microenvironment, so tumor immune surveillance and immune responses are different, leading to different results in immunotherapy.

Tissue-specific immune microenvironment

Immune cells are the main cellular components of tumor lesions, but the types and functions of immune cells infiltrating in different tumor microenvironments are very different.

• In brain tumors and uveal melanomas, the tumor infiltrates the least immune cells, and the macrophages dominate, surpassing lymphocytes and NK cells, and are resistant to immune checkpoint inhibitors.
• Lung adenocarcinoma, head and neck squamous cell carcinoma, skin melanoma, have the most immune cell infiltration, and have a good response to immunotherapy.
• Pancreatic cancer lesions have more immune infiltration, but macrophages are dominant. Pancreatic ductal carcinoma (PDAC) has more myeloid suppressor cells (MDSC) in the lesion area, which inhibits the function of infiltrating T lymphocytes and is resistant to immunotherapy.

The differences in the immune microenvironment across cancer species are driven by the APC and molecular characteristics of different tissues. In sterile tissues (pancreas, brain), filtration and metabolism tissues (liver, kidney), environmental interface tissues (skin, lungs, intestines), the number of microbes and other immunogens in daily contact are different, so the number and activity of APC are also different. .

Tertiary lymphatic structure of different cancer tissues

Most chronic inflammatory lesions are similar. There are ectopic lymphoid structures at the tumor lesion site, called tertiary lymphoid structures (TLSs), and a large number of B cells, CD4+ T cells and mature dendritic cells are found at the invasive edge.

More than 60% of NSCLC, CRC, PDAC, ovarian cancer and breast cancer lesions contain TLSs, 45% of HCC contain TLSs, and RCC is a uveal melanoma that has almost no such structure. The melanoma resection sample, about 10-30% of the original Primary lesions or skin metastases contain TLSs.

Tumor immune microenvironment affects clinical outcome

In melanoma, HNSCC, NSCLC, breast cancer, bladder cancer, urothelial cancer, and ovarian cancer, high-density tumor cytotoxicity and memory T cells and TH1 immune response are positively correlated with improving overall survival and disease-free survival.

Surprisingly, for renal cell carcinoma and prostate cancer, high CD8+ T cell density did not improve overall survival. In renal cell carcinoma, there are high levels of immature DC, Treg and other inhibitory immune cells, angiogenesis is abundant, and PD-L1 expression is high, so CD8+ T cells are polyclonal (not tumor-specific clones), low Toxicity (no anti-tumor effect) and other characteristics.

The real DC where the tissue resides is the most immunogenic APC, and it is the only APC that can efficiently present tumor cell antigens and activate the immune response. In addition to its role in draining lymph nodes, DC1s also contribute to the activation and expansion of T cells in TME, so DC1s may be a useful biomarker for immune checkpoint inhibitor therapy.

The enrichment of CD68 (pan-macrophage marker) positive cells improves the survival rate of colorectal cancer or prostate cancer, but melanoma, renal cell carcinoma, HNSCC, breast cancer, bladder cancer and pancreatic cancer have poor clinical effects. Maybe this marker is not accurate enough and contains various types of macrophages (for example, both M1 and M2 TAM), and more precise markers are needed to distinguish heterogeneous macrophages.

NK cell infiltration increases the survival rate of clear cell RCC, CRC and melanoma. Direct anti-tumor activity of NK cells: release granzyme, perforin, and express apoptosis-inducing proteins such as TRAIL, and indirect anti-tumor activity: release chemokines CCL5 and XCL1, and DC cell growth factor FLT3L, chemotactic DC to tumors , And promote its activation and proliferation. In non-small cell lung cancer, the activation receptors NKp30, NKp80 and DNAM1 of NK cells decrease, so although the number of NK cells increases, their function is impaired.

Mesenchymal cells affect tumor immunity

Most tumors include tumor parenchymal cells and mesenchymal components. Mesenchyme contains fibroblasts, pericytes and lymphoid tissues, lymphocytes, blood vessels, nerve cells, etc. embedded in the extracellular matrix (ECM) components.
In addition to lymphocytes, endothelial cells (ECs) and tumor-associated fibroblasts also affect anti-tumor immunity.

Tissue-specific vascular characteristics

The vascular system is highly specialized and adaptable to different organs, with different aggregation, pericyte coverage, and expression of adhesion molecules, all of which regulate vascular permeability and immune cell extravasation. The blood vessels of the liver are not arranged continuously, and ECs support the passage of immune cells. The retina and brain endothelium are characterized by tight junctions, which restrict the entry of immune cells.

In terms of tumors, new blood vessels (sprouting from the blood vessels of the host organ) have abnormal structures and increased permeability.

The difference between tumor blood vessels and normalized blood vessels (document)

In PDAC lesions, ECM falls into the tumor microenvironment, squeezes blood vessels, and causes vascular hypertension.
Glioma and RCC have a high degree of microangiogenesis.

The characteristics of the host tissue determine the organ-specific vascular characteristics, which are mainly determined by the local non-tumor cells, such as VEGF and bFGF secreted by vascular endothelial cells and fibroblasts, and the intrinsic characteristics of local site-specific endothelial cells.

Endothelial cells of different tissues express different pattern recognition receptors and cytokine receptors, and therefore have different responses to inflammation and injury.

Tumor blood vessels affect the immune cell components that infiltrate the tumor by controlling the extravasation of immune cells and the homing of immune cells. For example, inflammatory stem cells and hepatocellular carcinoma express CLEVER1 and VAP1, which contribute to the infiltration of Treg.

Tumor-specific fibroblasts

Fibroblasts are an important mesenchymal cell that secrete cytokines, chemokines, growth factors, and extracellular matrix to maintain local organ structure and homeostasis.

Tumor fibroblasts help tumors reshape the local microenvironment (document)

Tumor fibroblasts secrete HGF, FGF, etc. to promote cancer cell survival, proliferation and migration; secrete TGF-β, etc. to inhibit immunity, VEGFA, MMP9, etc. affect tumor angiogenesis and metastasis, and secrete chemokines to inhibit effector T cells to the tumor. Migration, expression of PDL1, etc., induce depletion of effector cells, etc.

Expert comment:

The immune microenvironment of tumors includes immune cells and mesenchymal cells that regulate immune cells. Different tissues have different tumor blood vessels and different immune microenvironments due to their structural differences, leading to differences in therapeutic response.

References：

Salmon H, et al. Host tissue determinants of tumour immunity, Nat Rev Cancer. 2019. Apr;19(4):215-227
Giraldo, N. A. et al. Tumor- infiltrating and peripheral blood T cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma. Clin. Cancer Res. 23, 4416–4428 (2017).
Ganss R. Tumour vessel remodelling: new opportunities in cancer treatment. Vasc Biol. 2020 Jan 14;2(1):R35-R43.
Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

(source:internet, reference only)

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