The immune response against cancer Maries van den Broek Institute of Experimental Immunology vandenbroek@immunology.uzh.ch
The immune system
Main cells of the immune system Dendritic cell Monocyte Macrophage Granulocyte B-cell T-cell Senses danger Presents antigen to T-cells Phagocyte in blood and tissue Production of toxic substances Production of antibodies Killer T-cells Helper T-cells All cells need to collaborate for an efficient immune response
T-cells must recognize cancer cells to kill them MHC T-cell receptor Cancer cell Antigen
Activation of the immune system To become activated the immune system requires: 1. Foreign structures (antigens) 2. Danger
Activation of the immune system To become activated the immune system requires: 1. Foreign structures (antigens) 2. Danger Pathogens are therefore efficiently recognized Cancer often does not provide sufficient antigens or danger Cancer patients have an immune response against their tumor, but often of insufficient quality
T-cell activation requires 3 signals that are often insufficient in cancer Signal 1: Antigen/MHC Signal 2: Co-stimulation Signal 3: Inflammatory cytokines
T-cell activation requires 3 signals that are often insufficient in cancer Signal 1: Antigen/MHC Signal 2: Co-stimulation Signal 3: Inflammatory cytokines
T-cell activation requires 3 signals that are often insufficient in cancer Signal 1: Antigen/MHC Signal 2: Co-stimulation Signal 3: Inflammatory cytokines
The immune response against cancer DC maturation Negative selection Escape - Ag loss - Regulation Mellman, Nature 2011
Tumor-associated infiltrate influences progression, immunity and response to therapy Pro-tumor Anti-tumor Hanahan & Coussens, 2012
Immune response to cancer 3 phases Elimination Equilibrium Escape Immune cells Cancer cells
Immune response to cancer Elimination
A high density of tumor-infiltrating memory T cells correlates with survival Tissue microarray of colorectal carcinoma stained for CD45RO (memory T-cells) Presence of tumor-infiltrating memory T cells correlates with prolonged survival Pagès et al., NEJM 2005
Tertiary lymphoid structures predict survival in lung squamous cell carcinoma TLS Retrospective cohort of 127 LSCC patients TLS Whole diagnostic cases, analysis of > 4 different tumor regions TLS Correlation of survival with Number of tumor-associated TLS Presence of germinal centers, i.e. TLS quality TLS Lung Karina Silina
Tertiary lymphoid structures predict survival in lung squamous cell carcinoma Early TLS Lymphocytic aggregate around CXCL13 blood vessel Primary follicle-like TLS Differentiated follicular dendritic cells (FDC) Secondary follicle-like TLS Germinal center (GC) CD23 CD21 DAPI Tissue segmentation Lymphocytic aggregate FDCs GC Other tissue Karina Silina
Tertiary lymphoid structures predict survival in lung squamous cell carcinoma Survival probability 1.00 0.75 0.50 0.25 Zurich cohort Progression free survival Groups TLS low / GC (n=66) TLS high GC (n=72) 1.00 0.75 0.50 0.25 Riga cohort Disease specific survival Groups TLS low / GC (n=34) TLS high GC(n=44) 0.00 p = 0.00069 0 1000 2000 3000 4000 0.00 p = 0.018 0 500 1000 1500 Days High density of GC TLS vs. All others Karina Silina
Immune response to cancer Equilibrium
Immune response to cancer Equilibrium Koebel, et al. Nature 2007
Immune response to cancer Escape
Immune response to cancer Escape Loss of antigen Patient ZH-311, metastasized melanoma Date Mar 2001 Jun 2001 Feb 2003 Mar 2004 Mar 2004 Aug 2004 Apr 2005 Sep 2005 Mar 2006 Sep 2006 Jul 2007 Apr 2008 Mar 2009 Jul 2010 Treatment First diagnosis inguinal lymph node metastasis: NY- ESO-1 Adjuvant Interferon a2a Interferon a2a and Temozolomid Elsidine Vaccinia/Fowlpox anti NY-ESO-1 vaccination Colon metastasis surgery Brain metastasis surgery and radiotherapy Anti NY-ESO-1 protein CpG vaccination Lung metastasis surgery Liver metastasis surgery Ipilimumab Abdominal wall metastasis surgery Stop Ipilimumab Death due to inoperable brain metastasis L von Boehmer et al. Cancer Immunity, 2013
Immune response to cancer Escape Loss of antigen A. NY-ESO-1 B. MHC I C. NY-ESO-1 D. NY-ESO-1 2001 LN met. 2001 LN met. 2004 Colon met. 2005 Brain met. E. NY-ESO-1 F. NY-ESO-1 G. NY-ESO-1 H. CD8 T cells NY-ESO-1 2008 Abd. wall met. 2006 Liver met. 2006 Liver met. 2008 Abd. wall metast. 2006 Lung met. Mar 2004 Vaccinia/Fowlpox anti NY-ESO-1 vaccination Sep 2005 Anti NY-ESO-1 protein CpG vaccination L von Boehmer et al. Cancer Immunity, 2013
Immune response to cancer Escape Local T-cell unresponsiveness -ve control experimental ve control Dysfunctional Melan-A-specific CD8 T cells in metastatic lymph nodes (LNs) and non-lymphoid tissue metastasis Zippelius A et al. Cancer Res 2004
Summary The 3 main obstacles for protective anti-tumor immunity are Insufficient innate signals Negative selection Local immunoregulation The tumor-associated stroma influences tumor progression and response to therapy, and is an attractive therapeutic target Local markers of adaptive immunity are associated with better survival Memory T cells GC TLS
Summary Equilibrium is mainly controlled by adaptive immunity Occurrence of donor-derived tumors in transplant recipients Outgrowth of transformed stable masses after depletion of T cells or T cell-derived effector molecules Escape results in clinically apparent cancer and is mediated by Loss of targeted antigen/mhc Locally compromised immunity many mechanisms
Targeting cancer on 3 levels Tumor cell Dendritic cell T-cell Cell death Antigen-release Inflammation Maturation Antigen-presentation Infiltration into tumor Survival in tumor Effector function
The immune system