LUNG CANCER AND COPD The two sides of the coin

1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra.Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

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

3. LUNG CANCER AND COPDThe two sides of the coin • 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?

4. T-cell inflammation in COPD: Emphysema Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:2445-54

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

6. Lung inflammation in smokers • 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 B-cells: oligoclonal lymphoid follicles Majo J, Ghezzo H, Cosio M. Eur Respir J, 2001;17:946-953 Saetta M Di Stefano A, Turato G et al: Am J Resp Crit Care Med;1998, 157: 822 Retamales J et al. Am j Respir Crit Care Med:2001; 164; 469

7. Adoptive transfer of pathogenic T Cells induce COPD-like Disease. Inflammation & emphysema with or without CS exposure 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. Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010

8. The autoimmune mechanism in COPD:the “steps” approach. N Engl J Med 2009;360:2445-54

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

10. 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

11. 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

12. 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

13. 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 patientsdeveloped 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.

14. GOLD IV 14% PLATINUM 1.5% BOLD 3.3% 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

15. Cox multivariate regression analysis of factors that predict lung cancer Variables included in the model: age, BMI, pack-year history, smoking status, GOLD, DLCO<80% and IC/TLC<0.25.

16. Cancer diagnosis in patients classified according to the DLCO

17. 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 5.69-3.08 5/29 associated with cancer: Systemic sclerosis 4.45 Discoid LE 4.24 Poymyositis/dermatomyositis 3.92 K. Hemminki: Eur Respir J 2011; 37: 463–474

18. 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.

19. 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. These patients should be followed more carefully and might benefit from screening programs

21. Resolution of inflammation:Regulons Inhibiting protein translation. Promoting mRNA decay STEP I and II The resolution of the immune response STEP 2 STEP 1 Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:2445-54

22. 1551 patients with COPD followed for 15 years Myeloid- derived suppressor cells (MDSCs) M1/M2 Alveolar Macrophages

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

25. 1551 patients with COPD followed for 15 years

26. Defining criteria for autoimmune diseases ( Witebsky’s postulates) Direct proof:Disease is reproduced in a normal recipient by direct transfer of autoantibody or T-cell transfer. 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: 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

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

28. Defining criteria for autoimmune diseases Direct proof:Disease is reproduced in a normal recipient by direct transfer of autoantibody or T-cell adoptive transfer. 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: Lymphocytic infiltration of target organ. Association with a particular MHC (Hla) haplotype.

29. Pathogenic T Cells Capable of Driving COPD-like Disease in Rag22/2 Mice • 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

30. Pathogenic T Cells are Capable of Driving COPD-like Disease in Rag22/2 Mice • 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. Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010

31. "Eccellenze in pneumologia Interventistica" La risposta immune nella BPCO. Unarelazione con ilcancrodipolmone? Manuel G. Cosio Marina Saetta. Napoli 2011

32. 1983

33. normal COPD

34. Pathogenic T Cells Capable of Driving COPD-like Disease in Rag22/2 Mice • 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

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

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

37. The original paradigm From BAL NE PR3 AZU elastase Oxidative stress MMP MME BREAKDOWN OF THE LUNG Low molecular weight elastin peptides Desmosine Hyroxiproline Only 20% develop COPD !! Why?? COPD

38. normal COPD

39. Correlation of alveolar wall inflammation and emphysema Saetta M et al. Am Respir Dis 1990; 141 1547-1552

40. Finkelstein R, Fraser R, Ghezzo H, Cosio M Am J Respr Crit Care Med 1995; 152:1666-1672

41. 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: 946-953

42. STEP I The innate immune response: Danger signals and TLRs. antigens Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:2445-54

43. regulation STEP II The adaptive Immune response: local lymphoid tissue, Dendritic Cells. Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:2445-54

44. STEP III Autoimmune lung Injury. Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:2445-54.

45. Cox multivariate regression analysis of factors that predict lung cancer Variables included in the model: age, BMI, pack-year history, smoking status, GOLD, DLCO<80% and IC/TLC<0.25.