The importance of CD4

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The importance of CD4

+

_{follicular helper T cells}

and tertiary lymphoid structures in the

anti-tumor immune response to breast cancer

Migliori Edoardo

INTRODUCTION... ERROR! BOOKMARK NOT DEFINED.

1. BREAST CANCER ... Error! Bookmark not defined.

1.1. THE BIOLOGICAL STRUCTURE OF THE MAMMARY GLAND ... Error! Bookmark not defined. 1.2. CLINICO-PATHOLOGICAL CLASSIFICATION ... Error! Bookmark not defined.

1.2.1. TMN STAGING ... Error! Bookmark not defined. 1.2.2. HISTOLOGICAL GRADING ... Error! Bookmark not defined. 1.2.3. HORMONE RECEPTOR AND GROWTH FACTOR RECEPTOR STATUS ... Error! Bookmark not defined.

1.2.4. MOLECULAR SUBTYPES ... Error! Bookmark not defined. 1.2.5. BC GENE PROFILING ... Error! Bookmark not defined. 2. TUMOR INFILTRATING LYMPHOCYTES ... Error! Bookmark not defined.

2.1. TIL INFILTRATION ... Error! Bookmark not defined.

2.1.1. TIL LOCALIZATION ... Error! Bookmark not defined. 2.1.2. TIL COMPOSITION ... Error! Bookmark not defined.

2.2. TIL AND PATIENT OUTCOME ... Error! Bookmark not defined.

2.2.1. TIL AND CLINICAL OUTCOMES ... Error! Bookmark not defined. 2.2.2. PROGNOSTIC AND PREDICTIVE VALUE OF TIL ... Error! Bookmark not defined. 3. HIGHLY ORGANIZED SITES FOR IMMUNE RESPONSE ... Error! Bookmark not defined.

3.1. SECONDARY LYMPHOID ORGANS ... Error! Bookmark not defined. 3.2. TERTIARY LYMPHOID STRUCTURES ... Error! Bookmark not defined.

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3.2.2.2. CXCL13 IN TLS NEOGENESIS ... Error! Bookmark not defined. 3.2.2.3. HEV DEVELOPMENT IN TLS FORMATION ... Error! Bookmark not defined. 3.2.2.4. NEGATIVE REGULATORS OF TLS FORMATION ... Error! Bookmark not defined. 3.2.3. TLS AND PATHOLOGY ... Error! Bookmark not defined. 3.2.3.1. TLS IN AUTOIMMUNE DISEASES ... Error! Bookmark not defined. 3.2.3.2. TLS IN CHRONIC INFECTION ... Error! Bookmark not defined.

3.3. TLS IN CANCER ... Error! Bookmark not defined.

4. IMMUNE RESPONSE CELLS IN TLS ... Error! Bookmark not defined.

4.1. REGULATORY CD4+_{T CELLS ... Error! Bookmark not defined.}

4.3.1. TREG PHENOTYPE AND DIFFERENTATION ... Error! Bookmark not defined. 4.3.2. TREG FUNCTIONS ... Error! Bookmark not defined. 4.3.3. TREG IN CANCER ... Error! Bookmark not defined.

4.2. FOLLICULAR HELPER T CELLS ... Error! Bookmark not defined.

4.1.1. TFH CELLS PHENOTYPE ... Error! Bookmark not defined. 4.1.2. TFH CELLS DIFFERENTATION ... Error! Bookmark not defined. 4.1.3. TFH CELLS FUNCTIONS ... Error! Bookmark not defined.

4.3. TFH CELLS IN HUMAN DISEASES ... Error! Bookmark not defined.

4.2.1. TFH CELLS IN AUTOIMMUNITY ... Error! Bookmark not defined. 4.2.2. TFH CELLS IN PRIMARY IMMUNODEFICIENCIES ... Error! Bookmark not defined. 4.2.3. TFH CELLS IN NEURODEGENERATIVE DISORDERS ... Error! Bookmark not defined. 4.2.4. TFH CELLS IN HIV ... Error! Bookmark not defined. 4.2.5. TFH CELLS IN CANCER ... Error! Bookmark not defined.

4.4. B LYMPHOCYTES ... Error! Bookmark not defined.

4.4.1. B CELLS PHENOTYPE AND DIFFERENTATION ... Error! Bookmark not defined. 4.4.2. B CELLS FUNCTIONS ... Error! Bookmark not defined. 4.4.3. B CELLS IN CANCER ... Error! Bookmark not defined. 5. OVERVIEW OF METHODOLOGICAL APPROACHES ... Error! Bookmark not defined.

5.1. TIL AND TLS DETECTION ... Error! Bookmark not defined. 5.1.1. H&E CONSENSUS ... Error! Bookmark not defined. 5.1.2. IHC STAINING ... Error! Bookmark not defined. 5.1.3. FLOW CYTOMETRY ... Error! Bookmark not defined. 5.1.4. TLS IDENTIFICATION BY GENE SIGNATURES... Error! Bookmark not defined.

AIMS OF THE STUDY ... ERROR! BOOKMARK NOT DEFINED.

6. AIMS OF THE STUDY ... Error! Bookmark not defined.

RESULTS ... ERROR! BOOKMARK NOT DEFINED.

7. RESULTS ... Error! Bookmark not defined. 7.1. TGF-β1 and IL-2 blockade induce CXCL13 production in CXCR5neg_PD1hi_ICOSint_{Tfh-like CD4}+_{T cells}

Error! Bookmark not defined.

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DISCUSSION ... ERROR! BOOKMARK NOT DEFINED.

8. DISCUSSION ... Error! Bookmark not defined. 8.1. MECHANISMS OF CXCL13 INDUCTION ... Error! Bookmark not defined.

8.1.1. TGF-β1 STIMULATION ... Error! Bookmark not defined. 8.1.2. IL-2 DEPRIVATION ... Error! Bookmark not defined. 8.2. TLS DETECTION ... Error! Bookmark not defined.

CONCLUSION AND PERSPECTIVES ... ERROR! BOOKMARK NOT DEFINED.

9. CONCLUSION AND PERSPECTIVE ... Error! Bookmark not defined.

ANNEXES ... ERROR! BOOKMARK NOT DEFINED.

10. SUPPLEMENTARY DATA: TGF-β1 and IL-2 blockade induce CXCL13 production in

CXCR5neg_PD1hi_ICOSint_{Tfh-like CD4}+_{T cells ... Error! Bookmark not defined.}

11. SUPPLEMENTARY DATA: Development of an immune gene signature for detecting tertiary

lymphoid structures in human breast cancer ... Error! Bookmark not defined.

12. CXCL13‐producing TFH cells Link Immune Suppression and Adaptive Memory in Human

The importance of CD4