The document summarizes the role of innate and adaptive immune cells in the tumor microenvironment and their effect on tumor growth. It discusses how the tumor microenvironment can influence immune cells and how immune cells can affect tumor progression. Key cells discussed include macrophages, neutrophils, NK cells, T cells, B cells, dendritic cells, and regulatory T cells. It covers topics like hypoxia, inflammation, immune evasion mechanisms used by tumors, and the pro-tumoral phenotypes that immune cells can adopt in the microenvironment.

1. “Innate and adaptive immune cells in the
tumor microenvironment and their role in
tumor growth.”
Presenter – Dr. Amit Samadhiya
Moderator – Dr. Alpana Saxena

2. Tumor Microenvironment - Normal cells, Molecules, Blood vessels that
surround and feed a tumor cell. A tumor can change its microenvironment,
and the microenvironment can affect how a tumor grows and spreads.

3.  Host reaction to tumor culminates in a chronic inflammatory environment.
Effector cells present in TME –
• Innate immunity – Macrophages
Neutrophils
NK cells
• Adaptive immunity - T – cells
B – cells
Dendritic cells

4. Characteristics of Tumor Microenvironment -
•Hypoxia
•Hypoglycemia
•Acidosis
•ROS
•Inflammation
Hypoxia inducible factor- 1 -
 Hetero-dimeric transcription factor of hypoxia responsive element.
α β
• α Subunit is oxygen labile.
• β subunit is constitutively expressed.
• Von Hippel Lindau tumor supressor protein forms E3 ligase complex.
OH
OH
pVHL
Proteasomal degradation.
NORMOXIC CONDITION
 All these stresses have compensatory adaptive cellular responses.

5.  Tumor microenvironment - A state of chronic hypoxia.

6.  HIF-1 induce transcription of more than 60 genes.

7. STRESS
(HYPOXIA)
STRESS RESPONSE
(i.e. TRANSCRIPTIONAL)
ANGIOGENESIS
 Physiologic vs Patho-physiologic response to Hypoxia.

9. Inflammation and cancer -
 Inflammation is a critical component of tumour progression. Many cancers arise from
sites of infection, chronic irritation and inflammation.
 In 1863, Virchow hypothesized that the origin of cancer was at sites of chronic
inflammation.
“wounds that do not heal”
(Dworak,1986)
 Subversion of cell death and/or repair programmes occurs in chronically inflamed
tissues, thus resulting in DNA replication and proliferation of cells that have lost
normal growth control.

10.  Chronic inflammatory conditions associated with neoplasm -
Pathologic condition Associated neoplasm
• Asbestosis
• Reflux esophagitis
• Cystitis
• Hepatitis
• Chronic cholecystitis
• Gastritis
• PID
• Obesity
Mesothelioma
Oesophageal carcinoma
Bladder carcinoma
Hepatocellular carcinoma
Gall bladder cancer
Gastric adenocarcinoma
Ovarian cancer
Breast and endometrial
cancer

11.  Induced self antigen recognition of tumor cells by NK cells and T-cells.
 Tumor cells escape this recognition by down-regulation of MHC-1 proteins.
MHC – 1 Defects
• Total, Haplotype or Allelic loss, Ranging 5-90%, depends on cancer type.
• Deregulation of MHC-1 antigen processing machinery (APM) components by
Hypermethylation of APM promoter region (6p21.3) and histone deacetylation.
• IFN-γ up-regulates MHC-1 expression. (NLRC5)
• Promoter methylation, copy number loss and somatic mutations most
prominent in NLRC5 among all MHC class I-related genes.

12.  NKG2D ligands can be upregulated in tumors in response to stress, infection
and malignant transformation resulting in enhanced activation of NK and T cells.
 NKG2D Ligands MICA, MICB & UL 16 binding protein down regulated in tumor
cells due to epigenetic changes such altered histone acetylation.

13. NKG2D receptors - C – type lectin like receptors, expressed on NK cells, γδ T
cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and
RAET1/ULBP families.

14.  The non-classical HLA-G molecule is a potent immune suppressor thereby impairing the
innate and adaptive immune response.
 HLA-G expression is mainly restricted to immune privileged cells/tissues, but found on tumor
cells of distinct origin or released as soluble factor (sHLA-G).

15.  Monocytes, in the presence of granulocyte–macrophage colony-stimulating factor
(GM-CSF) and interleukin (IL)-4, differentiate into immature dendritic cells.
 dendritic cells found in neoplastic infiltrates are frequently immature and defective in
T-cell stimulatory capacity.
 Soluble factors such as IL-6 and CSF-1, derived from neoplastic cells, push myeloid
precursors towards a macrophage-like phenotype.
 Among the innate and adaptive immune cells recruited to the tumor site, macrophages
are particularly abundant and are present at all stages of tumor progression.
 Substantial evidence indicates that macrophages, rather than being tumoricidal
adopt a protumoral phenotype in vivo both in the primary and metastatic sites.
 Experimental studies showing inhibition of tumor progression and metastasis by
ablation of macrophages, argue that immune cell engagement by tumors is essential for
their acquisition of a malignant phenotype.

18.  Tumor-Associated Macrophages in the Primary Tumor Promote Malignancy.

20. Role of Treg cells

21. Role of MSCs

22. Immunoediting

24. THANKYOU