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LUNG CANCER AND COPD The two sides of the coin Manuel G. Cosio (Padova/Montreal)

An adaptive immune inflammation, and probably autoimmunity, is important in the development of COPD. Could this inflammation be a factor in the development of lung cancer in smokers? LUNG CANCER AND COPD The two sides of the coin

T-cell inflammation in COPD: Emphysema Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:

From Lung tissue CD8+ inflammation in small airways Normal COPD Saetta M: Am J Respir Crit Care Med 1998;157:822–826.

Majo J, Ghezzo H, Cosio M. Eur Respir J, 2001;17: Saetta M Di Stefano A, Turato G et al: Am J Resp Crit Care Med;1998, 157: 822 T-cells in the lung are: Oligoclonal. Activated: CD4+ express a Th-1 profile CD8+ express perforin and granzimes. The inflammatory infiltrate persists after smoking cessation. These are signs of antigenic activation of the adaptive immune system Retamales J et al. Am j Respir Crit Care Med:2001; 164; 469 Lung inflammation in smokers B-cells: oligoclonal lymphoid follicles

Inflammation & emphysema with or without CS exposure Adoptive transfer of pathogenic T Cells induce COPD-like Disease. Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010 When T cells from cigarette smoke exposed mice are transferred to mice deprived of Tcells (Rag2-/-) they are able to induce emphysema even without further exposure to cigarette smoke.

The autoimmune mechanism in COPD: the “steps” approach. N Engl J Med 2009;360:

STEP 1STEP 2STEP 3 GOLD 0, I ? GOLD I, II ?GOLD III, IV? innate immunity Adaptive immunity AUTOIMMUNITY Tolerance failure. Genetic predisposition. Epigenetics ? COPD: EVASION AND PROGRESSION i m m u n i t y Resolution of inflammation: Regulons Inhibiting protein translation. Promoting mRNA decay tolerance

Immune system in smokers Immunosuppressed: DC presenting and maturation PMNs and AMs T-cell anergy B-cells Immunoglobulins Markers and mediators Martin R. Stämpfli: NATURE Reviews | Immunology; volume 9 | May 2009 | 377

1551 patients with COPD followed for 15 years 1.- Evasion/progression phenotype? 2.- Patient selection for studies 3.-Responses to treatment 4.- Searching for Biomarkers 5.- Understanding other comorbidities: cancer Data from J.M. Marin Trigo

Smoking, immunity, COPD and cancer. Working Hypothesis. Active adaptive immunity is important to defend against the development of malignancy. If normal smokers suppress immunity to avoid COPD, they would develop more cancers than smokers with severe COPD, who have very active adaptive immunity

Lung cancer in COPD A cohort of 2588 patients with COPD and without initial clinical or radiological evidence of lung cancer was followed for 62±38 months. A total of 222 of the 2588 COPD patients developed lung cancer for an incidence density of 15.8 cases/1000 persons year. The most frequent histological type was squamous cell carcinoma (44%). From Torres, Marin,… Saetta, Cosio, Celli ; unpublished.

Gold I: 48% adeno; 39% squam; 9% small cell;3% other Gold II: 35% adeno; 47% squam; 9% small cell; Gold III: 29% adeno; 46% squam; 21 small cell;4% other GOLD IV 14% PLATINUM 1.5% BOLD 3.3%

ParameterHazard Ratio95% CIp value Age DLCO<80% predicted BMI GOLD stage I II III IV Reference Cox multivariate regression analysis of factors that predict lung cancer that predict lung cancer Variables included in the model: age, BMI, pack-year history, smoking status, GOLD, DLCO<80% and IC/TLC<0.25.

Cancer diagnosis in patients classified according to the DLCO

Subsequent COPD and lung cancer in patients with autoimmune disease Standardized incidence ratios (SIRs) ( ratio of observed to expected) 297,300, patients 18/29 autoimmune diseases associated with COPD: SIR /29 associated with cancer: Systemic sclerosis 4.45 Discoid LE 4.24 Poymyositis/dermatomyositis 3.92 K. Hemminki: Eur Respir J 2011; 37: 463–474

Conclusions 1 Autoimmunity is the most likely mechanism for the development of severe COPD. In order to evade COPD smokers suppress their immune system. Suppression of the immune system could promote the development of cancer in smokers.

Conclusions 2 Smokers in Gold stages I and II (and possibly 0) and a low DLCO are at high risk for the development of lung cancer.Smokers in Gold stages I and II (and possibly 0) and a low DLCO are at high risk for the development of lung cancer. These patients should be followed more carefully and might benefit from screening programs These patients should be followed more carefully and might benefit from screening programs

STEP I and II The resolution of the immune response Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360: Resolution of inflammation: Regulons Inhibiting protein translation. Promoting mRNA decay STEP 1 STEP 2

1551 patients with COPD followed for 15 years Myeloid - derived suppressor cells (MDSCs) M1/M2 Alveolar Macrophages

% Napoli: 105 outpatient cases presenting with lung cancer. Napoli: 105 outpatient cases presenting with lung cancer. % of cancer diagnosed by Gold stages % of cancer diagnosed by Gold stages Prof. Serafino Marsico Dott.ssa Cecilia Calabrese % -

1551 patients with COPD followed for 15 years

Defining criteria for autoimmune diseases ( Witebsky’s postulates) Direct proof: Direct proof: Disease is reproduced in a normal recipient by direct transfer of autoantibody or T-cell transfer. Indirect evidence : Indirect evidence : Identify offending antigen in humans and reproduce the disease by experimental immunization. Isolation of autoantibodies or self-reactive T- cells from the organ. Circumstantial evidence: Circumstantial evidence: Lymphocytic infiltration of target organ. Association with a particular MHC (Hla) haplotype. Rose Noel and Bona Constantin Immunology Today 1993, 14, 426. Lambrecht B and Hammad H. Nature Reviews Immunology. 2003, 3, 994

Defining criteria for autoimmune diseases Direct proof: Direct proof: Disease is reproduced in a normal recipient by direct transfer of autoantibody or T-cell transfer. Indirect evidence : by experimental immunization. Indirect evidence : Identify offending antigen in humans and reproduce the disease by experimental immunization. Isolation of autoantibodies or self-reactive T- cells from the organ. Circumstantial evidence: Circumstantial evidence: Lymphocytic infiltration of target organ. Association with a particular MHC (Hla) haplotype.

Defining criteria for autoimmune diseases Direct proof: T-cell adoptive transfer. Direct proof: Disease is reproduced in a normal recipient by direct transfer of autoantibody or T-cell adoptive transfer. Indirect evidence : Indirect evidence : Identify offending antigen in humans and reproduce the disease by experimental immunization. Isolation of autoantibodies or self-reactive T- cells from the organ. Circumstantial evidence: Circumstantial evidence: Lymphocytic infiltration of target organ. Association with a particular MHC (Hla) haplotype.

Pathogenic T Cells Capable of Driving COPD-like Disease in Rag22/2 Mice Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010 T-cells oligoclonal: strongly implicates antigen-specific T-cells as mediators of disease pathogenesis. Transferred T-cells organ specific: only found in LUNG

Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010 Chronic cigarette smoke exposure generates pathogenic T-cells. Transfer of these cells into a T-cell deprived animal (Rag2-/-) induces many of the phenotypic changes associated with COPD. These changes, which occur without further exposure to cigarette smoke, are features indicative of autoimmunity. Pathogenic T Cells are Capable of Driving COPD-like Disease in Rag22/2 Mice

Eccellenze in pneumologia Interventistica" " Eccellenze in pneumologia Interventistica" La risposta immune nella BPCO. La risposta immune nella BPCO. Una relazione con il cancro di polmone? Una relazione con il cancro di polmone? Manuel G. Cosio Manuel G. Cosio Marina Saetta. Marina Saetta. Napoli 2011 Napoli 2011

1983

normal COPD

Pathogenic T Cells Capable of Driving COPD-like Disease in Rag22/2 Mice Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010 T-cells oligoclonal: strongly implicates antigen-specific T-cells as mediators of disease pathogenesis. Transferred T-cells organ specific: only found in LUNG

Evidence of autoimmunity Evidence of autoimmunity The reproduction of the disease in a normal recipientT-cell adoptive transfer, provides direct proof for autoimmunity (in animal models) and The reproduction of the disease in a normal recipient by T-cell adoptive transfer, provides direct proof for autoimmunity (in animal models) and supports the concept of an autoimmune mechanism in COPD.

% Napoli: 105 outpatient cases presenting with lung cancer. Napoli: 105 outpatient cases presenting with lung cancer. % of cancer diagnosed by Gold stages % of cancer diagnosed by Gold stages Prof. Serafino Marsico Dott.ssa Cecilia Calabrese

PR3AZUelastase BREAKDOWN OF THE LUNG NE MMP MME The original paradigmCOPD Only 20% develop COPD !! Why?? From BAL Low molecular weight elastin peptides Desmosine Hyroxiproline Oxidative stress

normal COPD

Correlation of alveolar wall inflammation and emphysema Saetta M et al. Am Respir Dis 1990;

Finkelstein R, Fraser R, Ghezzo H, Cosio M Am J Respr Crit Care Med 1995; 152:

Autoimmunity in COPD “If T-cells are responsible for the lung injury and progression of COPD, it would be as a response to an antigenic stimulus originating in the lung induced by cigarette smoking”. If that were the case, COPD could be considered an autoimmune disease triggered by smoking.” Majo J, Ghezzo H, Cosio MG. Eur Respir J, 2001; 17:

STEP I The innate immune response: Danger signals and TLRs. Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360: antigens

STEP II The adaptive Immune response: local lymphoid tissue, Dendritic Cells. Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360: regulation

Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360: STEP III Autoimmune lung Injury.

Cox multivariate regression analysis of factors Cox multivariate regression analysis of factors that predict lung cancer that predict lung cancer ParameterHazard Ratio95% CIp value Age DLCO<80% predicted BMI GOLD stage I II III IV Reference Variables included in the model: age, BMI, pack-year history, smoking status, GOLD, DLCO<80% and IC/TLC<0.25.